ArticlePDF AvailableLiterature Review

Heat-shock proteins, molecular chaperones, and the stress response: Evolutionary and Ecological Physiology

February 1999
Annual Review of Physiology 61(1):243-82

February 1999
61(1):243-82

DOI:10.1146/annurev.physiol.61.1.243

Source
PubMed

Authors:

Gretchen E Hofmann

University of California, Santa Barbara

Molecular chaperones, including the heat-shock proteins (Hsps), are a ubiquitous feature of cells in which these proteins cope with stress-induced denaturation of other proteins. Hsps have received the most attention in model organisms undergoing experimental stress in the laboratory, and the function of Hsps at the molecular and cellular level is becoming well understood in this context. A complementary focus is now emerging on the Hsps of both model and nonmodel organisms undergoing stress in nature, on the roles of Hsps in the stress physiology of whole multicellular eukaryotes and the tissues and organs they comprise, and on the ecological and evolutionary correlates of variation in Hsps and the genes that encode them. This focus discloses that (a) expression of Hsps can occur in nature, (b) all species have hsp genes but they vary in the patterns of their expression, (c) Hsp expression can be correlated with resistance to stress, and (d) species' thresholds for Hsp expression are correlated with levels of stress that they naturally undergo. These conclusions are now well established and may require little additional confirmation; many significant questions remain unanswered concerning both the mechanisms of Hsp-mediated stress tolerance at the organismal level and the evolutionary mechanisms that have diversified the hsp genes.

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December 22, 1998 14:39 Annual Reviews AR077-10

Annu. Rev. Physiol. 1999. 61:243–82



HEAT-SHOCK PROTEINS,

MOLECULAR CHAPERONES,

AND THE STRESS RESPONSE:

Evolutionary and Ecological

Physiology

Martin E. Feder

Department of Organismal Biology and Anatomy and Committee on Evolutionary

Biology, University of Chicago, 1027 East 57th Street, Chicago, Illinois 60637;

e-mail: m-feder@uchicago.edu

Gretchen E. Hofmann

Department of Biology, University of New Mexico, Albuquerque, NM 87131;

e-mail: ghofmann@unm.edu

KEY WORDS: hsp, temperature, protein denaturation and folding, inducible tolerance,

environmental gradients

ABSTRACT

Molecular chaperones, including the heat-shock proteins (Hsps), are a ubiquitous

feature of cells in which these proteins cope with stress-induced denaturation

of other proteins. Hsps have received the most attention in model organisms

undergoing experimental stress in the laboratory, and the function of Hsps at

the molecular and cellular level is becoming well understood in this context. A

complementary focus is now emerging on the Hsps of both model and nonmodel

organismsundergoingstressinnature,ontherolesofHspsinthestressphysiology

of whole multicellular eukaryotes and the tissues and organs they comprise, and

on the ecological and evolutionary correlates of variation in Hsps and the genes

that encode them. This focus discloses that (a) expression of Hsps can occur

in nature, (b) all species have hsp genes but they vary in the patterns of their

expression, (c) Hsp expression can be correlated with resistance to stress, and

(d) species’ thresholds for Hsp expression are correlated with levels of stress

that they naturally undergo. These conclusions are now well established and

may require little additional conﬁrmation; many signiﬁcant questions remain

243

0066-4278/99/0315-0243$08.00

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244 FEDER & HOFMANN

unanswered concerning both the mechanisms of Hsp-mediated stress tolerance

at the organismal level and the evolutionary mechanisms that have diversiﬁed the

hsp genes.

INTRODUCTION

Although heat-shock proteins (Hsps) ﬁrst achieved notoriety as gene products

whose expression is induced by heat and other stresses (1,2), discoveries of the

pastdecade haveshiftedthefocusof research to understanding therolesofHsps

as molecular chaperones (3–5). As a result, Hsps, their close relatives, their

molecularpartners, andmanynewlydiscovered proteinsare nowknownto play

diverse roles, even in unstressed cells, insuccessful folding, assembly, intracel-

lular localization, secretion, regulation, and degradation of other proteins (6);

failure of these activities is thought to underlie numerous and important human

diseases (7). Nonetheless, many of the questions of the past either remain

unanswered, awaiting the development of appropriate experimental tools, or

can now be revisited with new insights gleaned from the emerging understand-

ing of molecular chaperones. This review seeks to facilitate the examination or

re-examination of Hsps as responses to natural stress in diverse organisms in-

habiting environments outside the laboratory, the function of Hsps in tolerance

of natural stresses, and ecological and evolutionary variation in the heat-shock

system. The review sequentially considers (a) the principal implications of

laboratory-based studies for ecological and evolutionary research on Hsps, (b)

expression of Hsps in nature, (c) covariation of Hsp expression with environ-

mental and biological gradients of stress intensity, (d) the consequences of Hsp

expression for ﬁtness, and (e) evolutionary variation in Hsps and the genes

that encode them. The primary objective of this review is to redirect the focus

of evolutionary and ecological research on Hsps beyond the conclusions that

are now well-established and onto the many important questions that remain

unanswered.

STATE OF THE LITERATURE

Established Conclusions

The relevant literature on Hsps and molecular chaperones is huge, now com-

prising more than 12,000 references. Even a review of the relevant reviews

is difﬁcult. For this reason, we begin by describing several well established

conclusions and cite a fewof the manyexcellent recent reviews at diverse levels

of sophistication (4–6, 8–11).

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HEAT-SHOCK PROTEINS 245

The genes encoding Hsps (hsps) are highly conserved and occur in every

species in which they have been sought. Many of these genes and their prod-

ucts can be assigned to families on the basis of sequence homology and typical

molecular weight (6): hsp110, hsp100, hsp90, hsp70, hsp60, hsp40, hsp10,

and small hsp families. Gething (6) recognizes 7 additional families and 12

genes/proteins for which families have not yet been described. In eukaryotes,

many families comprise multiple members that differ in inducibility, intracel-

lular localization, and function.

Hsps function as molecular chaperones; i.e. they interact with other pro-

teins and, in so doing, minimize the probability that these other proteins will

interact inappropriately with one another. Hsps recognize and bind to other

proteins when these other proteins are in non-native conformations, whether

due to protein-denaturing stress or because the peptides they comprise have not

yet been fully synthesized, folded, assembled, or localized to an appropriate

cellular compartment. Binding and/or release of these other proteins is often

regulated by association with and/or hydrolysis of nucleotides. Typically, Hsps

function as oligomers, if not as complexes of several different chaperones,

co-chaperones, and/or nucleotide exchange factors. Interaction with chaper-

ones is variously responsible for (a) maintaining Hsps’ partner proteins in a

folding-competent, folded, or unfolded state; (b) organellar localization, im-

port, and/or export; (c) minimizing the aggregation of non-native proteins; and

(d) targeting non-native or aggregated proteins for degradation and removal

from the cell. Presumably, the last two functions are most important in coping

with environmental stress.

Not all Hsps are stress-inducible, but those that are respond to a variety

of stresses, including extremes of temperature, cellular energy depletion, and

extreme concentrations of ions, other osmolytes, gases, and various toxic sub-

stances. Activation of various intracellular signaling pathways results in Hsp

expression. All known stresses, if sufﬁciently intense, induce Hsp expression.

Accordingly, Hsps are equally well termed stress proteins, and their expression

is termed the stress response. A common aspect of these inducing stresses

is that they result in proteins having non-native conformations (12), which is

consistent with the function of Hsps as molecular chaperones.

Implications of the Published Literature for Ecological

and Evolutionary Studies of Hsps

Space limitations necessitate that we choose among numerous equally valu-

able references in preparing this review. To present both the breadth and depth

of research relevant to the evolutionary and ecological physiology of the heat-

shock response, we have compiled a near-comprehensive bibliography of

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246 FEDER & HOFMANN

that literature, which is available electronically (13) on the World Wide Web

in the Supplemental Materials Section of the main Annual Reviews site

(http://www.AnnualReviews.org).

A ﬁrst implication of this massive literature is that the Hsp ﬁeld has long ago

concluded its exploratory phase. Showing that an as-yet-unexamined species

expresses Hsps in response to heat or other stresses no longer has any particular

novelty.

Second, much of the work on Hsps outside the laboratory or in nonmodel

organisms was undertaken before the molecular diversity of Hsps and their

functionas molecular chaperones was obvious. In the interim, the experimental

tools for examining Hsps and the standards for such examinations have both

advanced considerably. As a result, much of the earlier work on evolutionary

and ecological physiology of Hsps regrettably either does not withstand current

scrutiny or contributes little to issues of current interest. Several issues are

obvious:

1. Many of the apparently singular Hsps of previous years, often detected

by one-dimensional electrophoresis and autoradiography, are now known

to represent entire families of Hsps, often with (a) discrete distributions

within the cell (e.g. cytoplasmic-nuclear, mitochondrial, chloroplast, or en-

doplasmic reticulum), (b) different degrees of inducibility (constitutively

expressed, constitutively expressed but increasing during or after stress, ex-

clusively inducible), (c) differing kinetics of induction and removal from

the cell, and (d) differing tissue speciﬁcity. Representing this diversity as

a single Hsp or two Hsps (“constitutive” and “inducible”) through use of

nonspeciﬁc probes or lysates of whole organisms and organs can obscure

phenomena of great signiﬁcance (e.g. compare Refs. 14 and 15 with 16).

This problem is sometimes remediable only with great difﬁculty. Often,

highly speciﬁc probes are available only for standard model organisms, par-

ticularly at the level of proteins, and great care must be taken in applying

these probes to non-standard organisms (17).

2. Inducible stress tolerance is increasingly understood to result from numer-

ous molecular mechanisms, of which Hsps are collectively only one. Other

mechanisms include synthesis of osmotic stress protectants such as polyols

andtrehalose, modiﬁcationsofthesaturationofcellmembranelipids(home-

oviscousadaptation), compensatory expression of isozymes or allozymes of

signiﬁcant enzymes, metabolic arrest, radical scavengers (superoxide dis-

mutase, glutathione system, cytochrome P450), and so on. Accordingly,

the unambiguous attribution of stress tolerance to Hsps in general or to

any speciﬁc Hsp requires more than correlative evidence (18–21). Increas-

ingly, proof resulting from genetic or direct experimental manipulation is

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HEAT-SHOCK PROTEINS 247

becoming the standard for establishing the functional or evolutionary sig-

niﬁcance of Hsps. Again, this rising standard is often met only with great

difﬁculty in ecological and evolutionary physiological studies, for many of

the techniques for genetic and experimental manipulation are not readily

applicable to the more ecologically and evolutionarily interesting species.

HSP-INDUCING STRESS IN NATURE

AND NATURAL INDUCTION OF HSPS

Depending on their geographic locale, organisms in nature risk exposure to

temperatures ranging from −100

◦

to more than 100

◦

C, and comparable ex-

tremes of chemical and gas concentration, food and water availability, hydro-

static pressure, radiation, and toxic substances of human origin. Seemingly,

Hsp expression should be a common occurrence in nature. In reality, how-

ever, movement and/or other behaviors may often enable organisms to avoid

Hsp-inducing stress in nature by exploiting equable microhabitats in otherwise

stressful environments (22–24). Also, biochemical specializations other than

Hsps may stabilize many organisms (or particular stages of their life cycles) so

that environmental extremes are not particularly stressful.

Even equable environments can contain Hsp-inducing microhabitats, and

even mild stresses can induce Hsps when multiple stresses act in combina-

tion. For these reasons, we can assume neither the presence nor the absence

of Hsp expression in nature; for that matter, we still do not know in any com-

prehensive sense whether wild organisms routinely, occasionally, or seldom

express inducible Hsps. A growing body of evidence, however, establishes that

at least in some circumstances and taxa, Hsp induction is not solely a laboratory

phenomenon.

One caution in evaluating the subsequent account is that organisms in na-

ture seldom undergo only one stress at a time. For example, an insect larva

undergoing natural heat stress in a rotting fruit may simultaneously experience

intense ultraviolet radiation, desiccation, and diverse alcohols and aldehydes,

among other stresses. This situation differs from that in most laboratory exper-

imentation, which involves one or a few stresses and makes attribution of Hsp

expression to a particular stress in nature more complicated.

Aquatic Temperature Stress

Due to the physical characteristics of water, the aquatic environment can be ex-

tremelystressful to its inhabitants.In general, the high speciﬁc heat and thermal

conductivity of water ensure that the majority of aquatic organisms will have

body temperatures equivalent to that of their surroundings. Furthermore, the

relative thermal homogeneity of aquatic environments can frustrate behavioral

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248 FEDER & HOFMANN

avoidance of thermal extremes. Some aquatic ectotherms nonetheless inhabit

thermally equable habitats or waters with enough thermal diversity to enable

behavioral thermoregulation; our focus is on those species that do not.

In the aquatic environment, habitual exposureto Hsp-inducing thermal stress

may be most common in sessile organismsthat occur in shallow, stagnant water

(e.g. ponds, tidepools, swamps, tidal ﬂats) or in the intertidal zone. Corals, for

example, routinely undergo thermal stress that results in bleaching, during

which the corals’ endosymbionts die. Even modest increases in water tempera-

ture of 1-2

◦

C can bleach corals; these temperatures also induce Hsp expression

in several species (25,26). Marine intertidal invertebrates undergo even larger

increases in body temperatures during tidal emersion (27–30). For example,

during aerial exposure intertidal mussels’ body temperatures exceed seawater

temperaturesbymorethan20

◦

C(31), resultinginHspexpression(29).Asimilar

phenomenonoccurs in encystedbrine shrimp (Artemia) embryos (32, 33). Even

relatively mobile aquatic ectotherms such as ﬁsh may undergo heat shock in

nature (34,35). For example, gobiid ﬁshes of the genus Gillichthys can become

trapped in shallow water, which is heated by the sun. Summer-acclimatized

ﬁsh have higher levels of Hsp90 in brain tissue than do winter-acclimatized

ﬁsh (34). In addition, the threshold Hsp induction temperature for one species,

G. mirabilis, is signiﬁcantly higher in summer than in winter. These data sug-

gest that seasonal variation in water temperature can alter the heat-shock re-

sponse. More exotic venues for aquatic thermal stress include thermal efﬂuents

ofpowerplants,hydrothermalvents,andthermalhotsprings, inwhichtemepra-

tures can exceed 100

◦

C (see Hsps of Archaea).

Terrestrial Temperature Stress

Unlike aquatic environments, terrestrial environments often offer diverse heat

sourcesand sinks and retreats that organismscan exploittoavoidthermal stress.

Thus, natural thermal stress and accompanying Hsp expression in terrestrial

environments typically involve limitations in mitigating thermal extremes by

movement and conﬂicts between thermoregulation and other needs. Salaman-

ders, for example, which ordinarily maintain cool temperatures in nature, can

inadvertently retreat beneath small sunlit rocks that become warm enough to

induce hsp70 mRNA expression (36); by abandoning these rocks to ﬁnd cooler

retreats they may risk immediate desiccation or even warmer temperatures.

The least equivocal case for routine exposure to Hsp-inducing temperature

stress is for plants, which cannot change location except as seeds or pollen and

can be limited in their ability to adjust heat exchange with the environment

(37). Thus, plants in nature can become extremely hot (38). By inference, the

entirerange of plant heat-shock responses (8, 39) should manifestthemselvesin

nature.Indeed, asmall number ofcasestudies document naturalHspexpression

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HEAT-SHOCK PROTEINS 249

(40–45),whichcanbegreatestattimesofdayorinregionsofanindividualplant

at which temperatures are highest (46). Plant species can differ dramatically,

however, in both the magnitude and diversity of the particular Hsps that are

expressed during days with especially warm weather (41). Plants should also

be prone to natural cold stress (47), which ought to induce expression of Hsps

(48–51).

Not surprisingly, therefore, many of the cases of natural thermal stress in an-

imals on land involve animals that live inside or on plants (e.g. 52). Drosophila

larvae and pupae encounter temperatures exceeding 40

◦

C if the necrotic fruit

they infest is in the sun, and express Hsp70 in response (53,54). Presumably,

other animals that cannot escape or offset intense solar heat loads will also

express Hsps in nature; this hypothesis awaits systematic study. A unique case

concerns desert ants, Cataglyphis, which voluntarily undergo body tempera-

tures of >50

◦

C, presumably to escape predators (55). The concentration of

Hsp70 family members increases in this species before it naturally encounters

high temperatures, as if in anticipation (56).

Terrestrial vertebrates are often especially effective in escaping heat stress,

but both they and invertebrates are occasionally hyperthermic during intense

physical activity, fever, or to conserve water. In birds and mammals, such hy-

perthermia activates HSF (the heat-shock transcription factor) and increases

the level of Hscs (Hsp cognates, constitutively-expressed Hsps) and Hsps

(57–59). Natural hypothermia of animals can be far more conspicuous than

natural heat stress, involving diapause, overwinteringin exposed sites, hiberna-

tion, and sometimes outright freezing. Diverseinsects expressHsps in response

tocoldshockor during overwinteringin diapause, although theidentityofthese

Hsps, their tissue speciﬁcity, and their developmental regulation vary greatly

(60–64). Some euthermic rodents express 70-kDa Hsps in response to cold

ambient temperatures, possibly in tandem with nonshivering thermogenesis

(65), and ground squirrels (Spermophilus) increase Hsp70 family members and

ubiquitin-protein conjugates during hibernation (66).

In summary, laboratory studies of the heat-shock response often have pro-

ceeded far in advance of ﬁeldwork that establishes an ecological context for

their interpretation. Documentation of both natural thermal stress and Hsp ex-

pression in nature can provide this context, and a small but growing number of

ﬁeld studies demonstrate that such documentation is feasible.

Inducing Stresses Other than Temperature

Virtually every nonthermal stress can induce Hsps (10, 67). Rarely, however,

are these nonthermal stresses ecologically relevant; the literature in this area

typically focuses on chemical stressors, and the corresponding data are es-

sentially pharmacological. Even when the stress in question is ecologically

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250 FEDER & HOFMANN

relevant, few studies of multicellular eukaryotes examine it in the ﬁeld or in

intact tissues and organisms. Some exceptional work, however, concerns plants

and brine-shrimp (Artemia). The resurrection plant, a desert species, expresses

Hsps in vegetative tissues during water stress; this expression is thought to

contribute to desiccation tolerance (68). Similarly, rice seedlings express two

proteins in the Hsp90 family upon exposure to water stress and elevated salinity

(69). Embryosof thebrineshrimp, oneofthemost hypoxia-tolerantmetazoans,

contain largequantities of p26, a molecular chaperone hypothesized to stabilize

proteins during long bouts of anaerobic dormancy (see Development). Clearly,

additional evolutionary physiological research in this area is sorely needed.

A recurrent theme is that thermal stress and these alternative stressors often

result in different patterns of Hsp expression, indicating a diversity of regula-

tory mechanisms. Examples include variation in the expression of Hsp70 and

ubiquitin in the Drosophila central nervous system under anoxia (70), and in

protein expression during osmotic shock in isolated ﬁsh gill cells (71).

Bioindicators

Owing to its responsiveness to diverse forms of stress, the heat-shock response

hasundergonewidespreadapplication in biomonitoring andenvironmental tox-

icology (72–75). In many cases, Hsps are especially useful biomarkers because

their induction is much more sensitive to stress than traditional indices such

as growth inhibition. The use of Hsps as biomarkers is most widespread in

aquatic toxicology. Most of the literature demonstrates elevated Hsp levels or

induction of Hsps under laboratory conditions and then proposes Hsps as a

potential indicator of pollutants or toxins in the environment. For example,

exposing freshwater sponges to pollutants extracted from river water elevates

Hsp70 levels, which increase still further when thermal stress is also imposed

(76). Additional examples of Hsp expression in aquatic toxicology concern ro-

tifers, (77), marine sponges (78), amphipods (79), polychaetes (80), mollusks

(81–84), and ﬁsh (85–87). Other applications purposefully deploy organisms

in potentially polluted aquatic systems as biosensors (88,89).

Intheterrestrialenvironment,whereheavymetalcontaminationandpesticide

or herbicide accumulation can be critical problems, common soil organisms

suchasinvertebrates(90)areusefulHsp-biomonitorsoftoxicants. Forexample,

centipedes (Lithobius) collected from near a smelter had higher Hsp70 levels

than those collected from unpolluted areas (91). Potentially, combinations of

heavy metals can induce such distinctive patterns of Hsp expression in soil

nematodes that these patterns can become diagnostic ﬁngerprints for speciﬁc

toxicants in soils (92).

Some aspects of the stress response, however, present problems for the use

of Hsps as biomarkers in environmental toxicology. Because so many different

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HEAT-SHOCK PROTEINS 251

stresses induce Hsps, investigators may be unable to attribute changes in Hsp

expression to any particular environmental stress. Organisms in the ﬁeld often

undergo multiple stresses simultaneously, the interaction of which can yield

signiﬁcantHsp expressionevenwhenno single monitoredtoxicantis at harmful

levels. Conversely, Hsps induced by another stress can enhance tolerance of

a toxicant whose presence is being monitored. Laboratory studies support the

difﬁculty of teasing apart environmental factors and attributing Hsp induction

to a single stressor. For example, freshwater sponges exhibit greater tolerance

of pollutants following a sublethal heat stress (76). Among the vertebrates,

diseased ﬁsh have elevated levels of Hsps in their tissues, and disease-related

expressionmayinterferewiththeuseofHspsasabiomarker(93).Thus, because

numerous factors can induce Hsp expression and stress tolerance, the utility of

Hsps as biomarkers of environmental toxins may be limited.

ENVIRONMENTAL AND BIOLOGICAL CORRELATES

OF THE HEAT-SHOCK RESPONSE

AND HEAT-SHOCK PROTEINS

Many investigators view correlations of organismal traits (e.g. Hsp expression)

and environmental or biological variables (e.g. level of environmental stress,

developmentalstage,distinctiveroleinaparasiticorsymbioticrelationshipwith

another species) as prima facie evidence of biological adaptation, and thus have

actively sought such correlations in terms of the heat-shock response. While

the probative value of such evidence in establishing adaptation has met with

skepticism (94), in this section we consider the evidence for such correlations,

whatever their meaning.

Variation in the Stress Response Along Environmental

Gradients of Stress

To understand how Hsps result in stress tolerance at the organismal level, many

investigators have characterized the stress response along gradients that occur

in nature. One central question is whether organisms from environments with

littlestress havea differentorreducedstress response compared with organisms

from environments with much stress. Little and much stress might correspond

to the center and edge of a species’ range, low versus high elevation, xeric and

hot versus mesic and cool climate, temperate versus tropical/polar latitude, low

versus high intertidal, and so on. In general, the resulting data support a corre-

lation among Hsp expression, stress tolerance, and gradients of environmental

stress. Thesegradients havereceivedunevenattention, however, and theirstudy

has yielded mixed results. Comparative studies across many degrees of latitude

have not produced the same results as studies of gradients on smaller scales

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252 FEDER & HOFMANN

(e.g. diurnal or microclimatic variation in stress). Currently, not a single study

has examined the stress response over the entire geographical distribution of

a species; thus, whether species at the extremes of their distributions have an

augmented heat-shock response is yet to be determined.

The majority of multi-species comparative studies focus on three aspects of

the stress response: the minimum (threshold) and maximum temperatures at

whichHspsareexpressedand/orarepresentincells,Hspconcentrationsincells,

and the diversity of the speciﬁc Hsps that are expressed. Except for the work on

threshold and maximum temperatures, much of this literature is a hodgepodge

of disconnected studies that are seldom comparable because of methodological

differencesand permitfewconclusionsotherthanthat speciesvaryinthedetails

of their stress response. Whether this variation has environmental correlates is

uncertain. A rare and exemplary exception is the work of Bosch and colleagues

on species of Hydra (95,96); below we discuss this and other similar work.

In general, the threshold temperature for Hspinduction is correlated withthe

typical temperatures at which species live, with thermophilic species having

a higher threshold than psychrophilic species. For example, a relatively cold-

water, northern species of mussel (Mytilus trossulus) has a lower threshold for

Hsp70 expession than its congener, M. galloprovincialis, a warm-water species

with a more southern distribution (97). Limpet species that occur in the upper

regions of the intertidal (Lottia digitalis and Lottia pelta) induce Hsps at 3–5

◦

higher than the threshold for limpets that occur lower in the intertidal (Tectura

scutum) (AL Haag & GE Hofmann, unpublished data). Subtidal species of

the marine snail Tegula exhibit much the same pattern (98). Aggregate ex-

pression of Hsp70 family members (17) occurs at 3–4

◦

C higher in Drosophila

melanogaster than in D. ambigua, a fruit ﬂy of Palearctic origin (56). The

same study reports a similar pattern for the desert ant Cataglyphis and Formica

polyctena, a red wood ant from a temperate climate. One remarkable outcome

oftheCataglyphisstudyisthat Hspsynthesis inthedesert antscontinues attem-

peratures up to 45

◦

C, whereas temperatures above 39

◦

C inhibit Hsp synthesis

in the temperate species. A similar pattern (although not as extreme) is evident

for desert and non-desert Drosophila (22). These results suggest that translation

itself may have an upper thermal maximum that varies among species adapted

to different temperature environments.

Antarctic organisms represent a special case of psychrophily because the

temperatures they experience are both extremely cold and extremely stable.

In combination, do these conditions result in the evolutionary loss of a heat-

shock response? In the subtidal alga, Plocamium cartilagineum, heat-inducible

hsp70 and ubiquitin transcription still occur, although the threshold is a spec-

tacularly cold 5

◦

C (99). Antarctic yeast species express Hsps at much lower

temperatures than does Saccharomyces, and at least one species lacks inducible

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HEAT-SHOCK PROTEINS 253

thermotolerance (100, 101). In Antarctic ﬁsh, the picture is not as clear. Al-

though a broadly cross-reactive anti-Hsp70 antibody can detect isoforms of

Hsp70 in various tissues of the ﬁsh Trematomus bernacchii, heat shock tempe-

ratures from 6 to 10

◦

C do not induce additional Hsp70 accumulation (GE

Hofmann, unpublished data). A member of the hsp70 gene family is present in

twoAntarcticﬁshspecies, T.bernacchiiandNototheniacoriiceps(ACWhitmer

& GE Hofmann, personal communication), and has been sequenced in Antarc-

tic ﬁsh species (102). At the other extreme, some hyperthermophilic Archaea

require temperatures in excess of 100

◦

C to induce Hsp expression (see Hsps of

Archaea).

Thermal stress gradients can be seasonal as well as geographic. In some

cases, both Hsp expression and thermotolerance increase during warm seasons.

The intertidal mussel Mytilus californianus displays signiﬁcantly different Hsp

induction proﬁles in summer than in winter, and summer-acclimatized mussels

induce Hsps at a threshold temperature that is 6

◦

C higher than the threshold

in winter-acclimatized mussels (103). However, whether the accentuated Hsp

expression in mussels in summer results in greater thermotolerance at the or-

ganismal level is unknown. Fish (34, 35) and intertidal invertebrates (31) also

vary seasonally in Hsp expression.

In addition to work we cite elsewhere, other studies examine geographical

gradients in ﬁsh (104, 105, 105a), maize (106), reptiles (107), and Drosophila

(108); intertidal gradients in limpets (27); diurnal temperature change in Droso-

phila (109) and intertidal mussels (29); diurnal variation in spruce trees (46);

and seasonal variation in insects (110).

One issue for future consideration is whether Hsps in general are specialized

to function at higher temperatures than other proteins (especially enzymes),

and whether homologous Hsps of species from various thermal environments

have corresponding variation in thermostability of function (111). For exam-

ple, that an Hsp’s resistance to thermal denaturation varies according to the

thermal niche of the species that expresses it has been demonstrated for only

a single Hsp, alpha-crystallin (112). Another issue is how differing thresholds

of Hsp expression have evolved, whether through mutations in HSF, general

thermostability of proteins and cells (113), or some other mechanism (114).

The Parasitic Environment

The roles of Hsps in host-parasite interactions have received considerable at-

tention from both clinical and biological perspectives, with the majority of the

research in two general categories. First, from the perspective of the host,

Hsps expressed by invading parasites are potent antigens that elicit an immune

response (115–117); parasites’ Hsps are thus potentially useful in generating

vaccines (118). From the perspective of the parasite, the synthesis of Hsps is a

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254 FEDER & HOFMANN

cellular defense mechanism that enables the parasite to live in different thermal

environments throughout its life-cycle (119). Parasites that infect mammalian

and avian hosts can undergo profound changes in temperature during the tran-

sition to these hosts (with internal temperatures of 37

◦

C or above) from ec-

totherm hosts or free-living stages. Induction of Hsps commonly accompanies

thistransition. Numerous studies havedemonstrateddevelopmentallyregulated

expression of Hsps in parasites; expression differs throughout the life-cycle

both quantitatively and in the types of Hsps that temperature change induces.

For example, mRNA transcripts for hsp70 and hsp83 homologues increase up

to 100-fold as Trypanosoma brucei leaves the tsetse ﬂy and enters a mam-

malian host (120). Aquatic snails release cercariae of the parasitic helminth,

Schistosoma mansoni, into freshwater; cercariae penetrate human skin and de-

velopintoadultworms,eventuallycausinglivercirrhosis. Thecercariaeexpress

two heat-inducible proteins that are not present in other stages (121).

Parasites that have an insect as the invertebrate vector have received much

attention with regard to the developmentally regulated expression of Hsps. Ex-

amples include parasitic nematodes (122); cestode parasites (123); the malarial

organism Plasmodium (124); Borrelia burgdorferi, the etiological agent of

Lyme disease (125); the protist Leishmania (126); Trypanosoma cruzi (127);

and Theileria (128).

Some parasite life cycles do not involve an animal vector; a free-living stage

of the parasite occurs in water or soil and enters the host. In several cases,

induction of Hsps accompanies the transition from the environment into the

host. Inthefungal parasiteHistoplasmacapsulatum, thetemperature shiftupon

infection of a mammalian host cues both the transformation from a mycelial

form to a budding yeast morphology and the expression of Hsps (129,130).

Eimeria, an intestinal parasite of numerous animals, expresses Hsp90 during

infective life stages. Eimeria parasites are particularly interesting because this

genus infects diverse hosts with correspondingly diverse body temperatures

(e.g. marine ﬁsh, poultry, and cattle). However, speciﬁcity of infection is high

at the species level, e.g. cattle are the exclusive host for Eimeria bovis (131).

Whether the heat-shock response of Eimeria co-evolved with its speciation into

these hosts is an open question.

Finally, the heat stress that infective life cycle stages of parasites experience

is as diverse as their hosts. In nature, parasites of ectotherms can encounter

dramatic shifts in temperature when their hosts’ body temperature varies, as has

been reported for parasites of reptiles, ﬁsh, and intertidal organisms (132,133).

Symbiosis

Just as Hsps may play an important role in parasitism, in which one species

maintains a close but antagonistic relationship with others, they also function

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in symbiosis, in which interspeciﬁc relationships can be equally close but not

adversarial. Perhapsthe mostgeneral example of this point concerns mitochon-

dria and chloroplasts, which evolved from endosymbionts that colonized other

cells early in the history of life. These organelles often require proteins that

are encoded in the nuclear genome and synthesized by the host cell, and hence

must be imported into the organelle. Hsps play diverse roles in this process in

mitochondria. A cytoplasmic Hsp70 family member maintains peptides in an

unfolded conformation, which enables the peptides topass through pores inthe

mitochondrial membrane; a mitochondrial Hsp70 is part of theprotein machin-

ery that imports the peptide; and the Hsp60/Hsp10 apparatus participates in the

folding of the imported protein (134). Several groups of primitive eukaryotes

contain still other endosymbiotically derived organelles, the hydrogenosome

and the nucleomorph, whose Hsps share a characteristic sequence with those

of mitochondria and proteobacteria (135–138). The Hsp sequence similarities

have been used to suggest that hydrogenosomes may derivefrom mitochondria,

share a common origin with mitochondria, or represent independent coloniza-

tions of early eukaryotic cells (135–137, 139).

Asidefromendosymbioticallyderivedorganelles,thebest-studiedsymbioses

concern bacterial endosymbionts that infect insects, including aphids, ﬂies,

ants, and cockroaches. Aphids, for example, harbor the bacterium Buchnera in

specializedcells(bacteriocytes)within a distinctive structure in the body cavity,

the bacteriome (140). The bacteria express a protein, symbionin, at especially

high levels, and this protein is a member of the GroEL (Hsp60) family. Other

bacterial chaperones, including GroES (Hsp10) and DnaK (Hsp70), are also

present at high levels (140). A similar phenomenon is evident in tsetse ﬂies

(141).

The function and signiﬁcance of these high Hsp levels is enigmatic. The

Hsps apparently are not a response of the endosymbionts to a novel (and there-

fore stressful) host environment, as the Buchnera/aphid symbiosis is 150–250

million years old. The endosymbionts, however, havebeen evolving at an espe-

ciallyhigh rate; thus, theelevatedmolecularchaperones could be compensating

for decreased protein stability due to the accumulation of numerous amino acid

substitutions (142,143). Nonetheless, the bacteria themselves can mount a

strong heat-shock response when their host undergoes stress (144). Other rel-

evant symbioses include X-bacteria in the symbiosomes of Amoeba (e.g. 145),

Bradyrhizobium and Rhizobium in the root nodules of nitrogen-ﬁxing plants

(146), and the zooxanthellae component of corals (26, 30). A recurrent theme

is that the endosymbionts modify the amount and/or diversity of Hsps present

in the symbiosis. In some cases, this modiﬁcation is thought to contribute to

the maintenance of the endosymbionts within the host, and in others to the

augmentation of the heat-shock response of the symbiosis as a whole. Finally,

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256 FEDER & HOFMANN

Wolbachia, a bacterial endosymbiont that infects millions of arthropod species,

both interferes with the mating of infected and uninfected hosts and can alter

their constitutive expression of Hsp70 and Hsp90 family members (147). Sim-

ulated natural heat stress can diminish this reproductive interference, possibly

by overriding the symbiont’s effect on the host Hsps.

Development

Many species exhibit characteristic and distinctive patterns of Hsp expression

(ornonexpression)duringthe variousstagesofdevelopment,includinggameto-

genesis, embryogenesis, and metamorphosis (e.g. 148–151). These patterns are

oftenconsistentwithenhancedstressresistanceindevelopmentalstagesthaten-

counter unusual levels of environmental stress or during circumstances such as

dormancyand diapause (see below). In other cases, developmental programs of

Hsp expression ensue even in the absence of any obvious environmental stress.

One common pattern is that one or more Hsps are not expressed in the initial

phases of embryogenesis (152–156) or late in gametogenesis (157–161), pos-

sibly because Hsps can be harmful to developing cells (see Deleterious Aspects

of Hsps). Parental provision of Hsps or hsp mRNAs can sometimes override

gametic or embryonic absence of Hsp expression (162,163); in other cases this

absence presumably poses a signiﬁcant problem for continued development

in the face of stress (164). Stress not only can kill vulnerable developmental

stages outright, but also can produce lasting damage to surviving organisms,

such as the phenocopying of genetic defects; Hsps may minimize such defects

(165,166).

Adaptational analyses of the developmental expression of Hsps are diverse.

Some plant seeds presumably must endure extremes of heat, desiccation, and

other stresses before germinating, and some must germinate under especially

challenging conditions. However, although seeds clearly undergo developmen-

tally regulated expression of Hsps and embryos can express Hsps in response

to environmental stress (167–169), few investigators have considered whether

these patterns of expression are ampliﬁed or modiﬁed in species and ecotypes

that naturally encounter especially challenging stress regimes (68, 170). Our

stateofknowledgeis similar for fungal spores, which expressparticularHsps in

a developmentally regulated program (e.g. 171,172). Several interesting case

studies are available for animals, although a general pattern is yet to emerge.

In the most spectacular example, encysted brine-shrimp (Artemia) embryos

undergo developmental arrest, in which they may survive for years without

environmental water or oxygen. The encysted embryos accumulate enormous

concentrations (15% of total protein) of a small Hsp (173–177) and treha-

lose (178), and suppress ubiquitination of damaged proteins (179). Non-adult

D. melanogaster infest necrotic fruit, which can become extremely warm if it

is sunlit (53,54); this species mounts a massive heat-shock response, which

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HEAT-SHOCK PROTEINS 257

is greatest in the developmental stages that presumably undergo the most ex-

posure to natural heat stress (18,19,180). Other ﬂies overwinter while at a

particular developmental stage, and undergo considerable Hsp expression in

response to cold (60–63). Later in development, ubiquitin may assist in the

degeneration of ﬂight muscles that are no longer needed after nuptial ﬂights of

insects (181). Finally, the temperature threshold for expression of Hsps may

itself undergo modiﬁcation; e.g. the threshold decreases in mammalian testis,

in which gametogenesis normally occurs at lower temperatures than in the core

of the body (182,183).

Aging and Senescence

As mammals age, damage to proteins progressively accumulates, and both the

ability to express Hsps (e.g. Hsp or hsp mRNA levels after a standard exposure

to heat or other stress) and stress tolerance deteriorate (184,185). Moreover,

individualHspscan become less able to mitigate the effectsof stress on proteins

as mammals age (186). In ecological and evolutionary terms, whether similar

Hsp-aging relationships are important or even evident in wild organisms is

unknown,althoughtheserelationshipsoccurindiversespeciesinthelaboratory:

Drosophila (187,188), nematodes (189–191), and Daphnia (192).

These ﬁndings have provoked great interest in how Hsps potentially affect

senescence and lifespan. A unifying hypothesis in the foregoing work is that

proteindamage, due primarily to oxidation/free radical activity, gradually accu-

mulates during the life of a cell or organism and can lead to death if unabated;

Hsps and other molecular stress responses ordinarily can mitigate this dam-

age to some extent, and the decreasing expression of Hsps with age therefore

contributes to mortality. If this hypothesis is correct, then treatments that both

reduce damage to protein and increase Hsp expression (e.g. heat shock) should

prolong life. In nematodes (Caenorhabditis elegans), some single-gene muta-

tions that increase lifespan are associated with increased thermotolerance, but

through as-yet-undescribed mechanisms (189–191). In Drosophila, heat shock

extends lifespan (193), and this extension is enhanced in ﬂies transformed with

additional copies of the hsp70 gene (194). Nutrient deprivation can also extend

lifeinrodents,presumablybyreducingthemetabolicrateandconsequently,ox-

idative damage to proteins; starvation, however, variously increases, decreases,

or has no effect on Hsp expression (195–199).

FITNESS CONSEQUENCES OF HSP EXPRESSION

General Issues and Beneﬁcial Aspects of Hsps

Understandingthe consequences of variationin Hspsandthestress response for

Darwinian ﬁtness requires a detailed appreciation of the mechanisms by which

Hsps mitigate the impact of stress on individuals in natural populations. These

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258 FEDER & HOFMANN

mechanisms are becoming well understood at the level of model proteins with

whichHspscaninteract, butareprogressivelylesswellunderstoodatthelevelof

the cell, tissue, organ, and whole organism. At the level of the model protein,

various stresses clearly either directly or indirectly result in conformational

change, and Hsps typically promote the reacquisition or maintenance of the

native structure and function by minimizingthe tendencyof non-native proteins

to interact inappropriately (200,201). In cells, stress-induced conformational

change, protein aggregation, and molecular chaperoning of model proteins are

also well established (200–202), and many cellular components differin stress-

tolerant and stress-intolerant cells (67).

Two primary issues impede the linkage of variation in these well-established

mechanisms and phenomena to variation in the ﬁtness of individual complex

multicellular eukaryotes. First, is the variation in sensitivity to stress among

cells, cell types, tissues, organs, and organisms attributable to a small number

of critical lesions, especially sensitive targets of stress and functions of speciﬁc

Hsps in protecting or repairing these lesions/targets? Or is variationin sensitiv-

ity to stress an aggregate function of a widespread and diverse impact of stress

on cellular structures, with Hsps mitigating multiple lesions in diverse ways

(21)? The former alternative may be more analytically tractable than the latter.

Second, given that cells and organisms may have multiple Hsps in each Hsp

family, multiple Hsp families, and multiple non-Hsp mechanisms of stress mit-

igation, howcan we unambiguously establish the contributionor importance of

anyparticularHsp, Hsp family,ormechanism in the complexcell, tissue, organ,

or organism? Much of the published literature on the functional consequences

of Hsp expression for whole organisms or the cells they comprise runs afoul of

these issues. Literally thousands of studies report correlations between Hsp ex-

pression, diverse biological functions in the face of stress, and stress tolerance,

but these typically conclude that their ﬁndings are at best consistent with a role

of one or more Hsps in stress tolerance. Evaluating the roles of single factors

in complex systems is an ongoing challenge in most areas of the biological

sciences, and the heat-shock ﬁeld largely has not yet deployed counterparts of

the solutions that other ﬁelds have developed.

One conspicuous and major exception includes techniques and approaches,

primarily drawn from molecular biology and genetics, that allow the manipu-

lation of individual Hsps or speciﬁc genes that encode them. In rare instances,

a species naturally may have an unusual genetic system (203) or a diminished

suite of Hsps (95,204) that accomplishes the same end; also, several chemical

compounds may speciﬁcally inhibit one or more Hsps (e.g. 205,206). The gen-

eral implication of the resulting work (Table 1) is that, even in whole organisms

or the cells they comprise, variation in single Hsps can be consequential for

ﬁtness. Some speciﬁc implications are as follows: Individual Hsps can have

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HEAT-SHOCK PROTEINS 259

Table 1 Phenotypes of multicellular eukaryotes, and the cells and tissues that they comprise,

for which Hsps are necessary and/or sufﬁcient

Protein Phenotype

Hsp10 Cellular: tolerance of ischemia (no phenotype) (308); tolerance of ischemia when

co-expressed with Hsp60 (308)

Hsp27 Cellular: resistance to chemotherapeutic drugs (309); resistance to hydrogen

peroxide (310,311); resistance to hydrogen peroxide (no phenotype) (312);

resistance to ultraviolet radiation (no phenotype) (312); resistance of tumor

cells to monocytes (311); sensitivity to lymphokine-activated killer cells (no

phenotype) (311); tolerance of hyperthermia (312–316); resistance to tumor

necrosis factor (317) (310); tolerance of ischemia (318); resistance of actin

polymers to cytochalasin (314); accelerated nuclear protein aggregation (319);

accelerated decline of thermal radiosensitization (319)

Crystallin Cellular: tolerance of hyperthermia (320,321); tolerance of ischemia (318);

resistance to tumor necrosis factor (310); resistance to hydrogen peroxide (310)

Hsp60 Cellular: tolerance of hyperthermia (no phenotype) (322,323); tolerance of

ischemia (no phenotype) (308,322, 323); tolerance of ischemia when

co-expressed with Hsp10 (308)

Hsp65 Cellular: tumor regression (324); loss of tumorigenicity (325)

Tissue/organ: regression of malignant tumors (324)

Hsp70 Cellular: tolerance of hyperthermia (326) (316, 322, 323, 327–342); tolerance of

ischemia/hypoxia (322, 323, 340, 343–345); recovery from translational and

transcriptional inhibition following heat shock (335); regulation of heat-shock

response (331,346, 347); tolerance of endotoxin (348); reduced protein

denaturation upon heat exposure (349); tumorigenicity (350); cell proliferation

(351,164); resistance to hydrogen peroxide (311); resistance of tumor cells to

monocytes (311); sensitivity to lymphokine-activated killer cells (no phenotype)

(311); escape from drug-induced cell cycle arrest (352); protein glycosylation

(353); tolerance of ultraviolet radiation (354); apoptosis (351,355,356);

resistance to apoptosis (no phenotype) (328,329)

Tissue/organ: recovery of contractility after ischemia (345, 357–359); reduction

in myocardial infarct size (345,359); reduction of hyperthermic damage to

midgut (221); resistance of heart to ischemic injury (357–359); resistance of

hippocampus to ischemic injury (360)

Organismal: tolerance of hyperthermia (18–20, 109, 156, 203, 221, 224, 278, 361);

growth and development (222); regulation of heat-shock response (361);

persistence in nature (no phenotype) (277)

Hsc70 Organismal: tolerance of hyperthermia (203)

Hsp72 Cellular: apoptosis (no phenotype) (362); protection against heat-induced nuclear

protein aggregation (319); protection against hypoxia (363); protection against

thermal radiosensitization (319)

Tissue/organ: reduction in myocardial infarct size (364)

Grp78 Cellular: protein secretion (229–231)

(Continued)

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260 FEDER & HOFMANN

Table 1 (Continued)

Protein Phenotype

Hsp90 Cellular: tolerance of hyperthermia (322,323,328, 329,340); tolerance of

ischemia (no phenotype) (322, 323, 340); apoptosis (362); apoptosis

(no phenotype) (328, 329); cell proliferation and cell cycle control (365);

glucocorticoid receptor function (205)

Hsp100 Organismal: host infection in Leishmania (126)

Hsp101 Cellular: tolerance of hyperthermia (366)

Many Hsps Cellular: recovery of cell proliferation after heat shock (367); recovery from

chromosome damage after heat shock (367–369); tolerance of hyperthermia

(370, 371); tolerance of ischemia (336)

HSF Organismal: oogenesis and development (372); thermotolerance (372, 373)

In all cited work, speciﬁc Hsps have undergone experimental or natural manipulation.

pleiotropic effects, interacting with multiple systems in diverseways. Findings

from manipulations of individual Hsps usually (but not always) are consistent

with the outcome of correlative studies (see above). Finally, despite the huge

body of work on Hsps and the growing use of manipulative techniques, we

have remarkably little physiological insight into exactly how the activity of

Hsps culminates in the enhanced stress tolerance of multicellular eukaryotes

and the cells and tissues that they comprise.

Interestingly, one clear conclusion that correlative studies have yielded is

that Hsps cannot account for the entirety of inducible stress tolerance (207–

217). Indeed, some component of inducible stress tolerance may be unrelated

to protein synthesis in general (214,218, 219).

Deleterious Aspects of Hsps

The many advantages of the heat-shock response suggest that natural selection

should maximize the expression of Hsps. By contrast, the genes encoding Hsps

have not undergone unlimited ampliﬁcation in the genome, and the Hsps them-

selves are subject to strict autoregulation by multiple molecular mechanisms

(220). These contrary ﬁndings suggest that Hsps can have both positive and

negativeimpacts onﬁtness, and that natural selectionmayhave acted to balance

these impacts in setting the level of Hsp expression. For example, while small

to moderate increases in Hsp70 levels enhance inducible thermotolerance in

Drosophila, large increases in Hsp70 levels actually decrease thermotolerance

(221); evolution thus may favor an intermediate level of Hsp70. A common

theme in related work is that high levels of Hsps may be especially detrimental

to cells or developmental stages in which cell growth and division proceed at

high rates. Drosophila larvae transformed with extra copies of the hsp70 gene

have greater larva-to-adult mortality and slower development than do control

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HEAT-SHOCK PROTEINS 261

larvae; these strain differences are proportional to the number of Hsp-inducing

heatshocks administered to the larvae(222). LarvaenaturallyvaryinginHsp70

expression display a similar pattern (223). Drosophila cells engineered to ex-

press Hsp70 constitutively at ﬁrst grow more slowly than control cells, but

subsequently resume control growth rates once the Hsp70 is sequestered from

the cytoplasm (164); indeed, Drosophila embryos remove Hsp70 from their

cells rapidly after heat shock (224). A yeast strain that cannot express Hsp104

grows faster than its wild-type counterpart on some media (171). More gen-

erally, most animal species that have been studied do not mount a heat-shock

responseduringearlystagesofembryogenesis(seeDevelopment),whenprotein

synthesis may be especially intense.

These negative effects may have at least two nonexclusive explanations

(222,225, 226): First, Hsps at high concentration could be toxic, directly in-

terfere with ongoing processes in the cell, or otherwise alter function to the

detriment of the cell (220). Second, the synthesis and degradation of Hsps

could consume an intolerably large fraction of a cell’s or organism’s nutrient

and energy stores, and/or occupy so large a fraction of the synthetic/catabolic

apparatusthattheprocessingofotheressentialbiomoleculessuffers(226–228).

Consistent with the ﬁrst explanation, cellular sequestration of Hsp70 is corre-

lated with the resumption of proliferation in cells constitutively expressing this

protein (164). Also, overexpression of an Hsp70 family member inhibits pro-

tein secretion and reduction increases secretion in mammalian cells in culture

(229–231); excess amounts of another Hsp70 family member canpromote pro-

tein aggregation in vitro (M Borrelli & J Lepock, personal communication);

and Hsp70 can perturb the normal structures of nascent polypeptides (232).

Tests of the second explanation have manipulated the costs of or resources

for Hsp expression. Growth of corn in nitrogen-rich soil increases the syn-

thesis of Hsps in response to a standard heat shock (233); in plants grown in

nitrogen-poor soil, other proteins may be catabolized to supply amino acids

for synthesis of Hsps (234). These ﬁndings suggest that Hsp synthesis can be

nitrogen-limited in plants. Starvation reduces the expression of Hsp 70 family

members in mice (195). In Drosophila larvae, by contrast, co-expression of

β-galactosidase and Hsps has no greater cost for growth and development than

does expression of Hsps alone (225). Further study of this apparent trade-off of

the beneﬁts and disadvantages of Hsp expression, moreover, has the potential

to link evolutionary and mechanistic views of this problem that heretofore have

been separate (222,225).

MICROEVOLUTIONARY VARIATION IN HSPS

Hspsareroutinelytoutedasadaptationsthataroseandaremaintainedvianatural

selection for stress resistance. Origin and maintenance of a trait by selection

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262 FEDER & HOFMANN

require that it vary within populations, and that this intra-population variation

have a genetic basis and affect the Darwinian ﬁtness of individuals. Here we

ask whether Hsps, the genes that encode them, and the factors that modify

their expression display such patterns of variation and undergo stabilizing or

directional selection in response to environmental stress.

First, not all intrapopulation and intraspeciﬁc variation results from genetic

differences. For example, seasonal acclimatization and temperature acclima-

tion in the laboratory can alter the minimum temperature at which Gillichthys,

a gobiid ﬁsh, expresses an Hsp90 family member (34,235). Seasonal acclima-

tization likewise affects Hsp70 levels in mussels (Mytilus) (103), and routine

culture temperature affects the magnitude and temporal pattern of Hsp expres-

sion in HeLa cells (236). Such changes may stem from alterations in the cellu-

lar environment that modify the activation of HSF (113,182, 236,237). These

changes, however, are not universal; laboratory thermal acclimation does not

alter the thermal sensitivity of Hsp expression in ﬁsh hepatocytes in culture

(238), Drosophila larvae (19), and mussels (103).

Evenwhenacclimationandseasonalchangearecontrolled,however, individ-

uals within a population or species may varyin Hsp expressionand/or the genes

that determine it. Relevant research has examined this issue on two levels: di-

rectsequencevariationandrestrictionfragmentlengthpolymorphisms(RFLPs)

(240). Thesequenceof hsp70 variesamongstrainsof the parasiteTrypanosoma

(241,242) andthenematode C. elegans (243), and among conspeciﬁcsforsome

but not all of the mammalian hsp70 family members (240), as does that of the

untranslated region of hsp27 in normotensive and hypertensive rats (244).

RFLPs consistent with intraspeciﬁc variation either in the hsp genes or ﬂanking

regions are detectable in the hsp60 and hsp70 of the spirochete Borrelia (245),

in multiple hsp70 family members of mammals (240,246, 247), and in several

plant species (248–250). One putative instance of intraspeciﬁc variation in hsp

copy number concerns D. melanogaster, in which at least ﬁve nearly identical

copies of hsp70 occur at two chromosomal loci. At locus 87A7, two copies are

arranged as an inverted repeat (251,252); at 87C1, two copies ﬂank a region

containing at least one additional copy (252,253) plus numerous α/β repeats,

which encode heat-inducible mRNAs of no proven function (254–257). Up

to ﬁve additional hsp70 copies have been reported, with copy number varying

among strains and time of year (253,255, 258–261). However, these reports

either cannot exclude that such variation is actually in intergenic regions or that

the reports are for Drosophila cells in culture or mutagenized laboratory strains

rather than wild or even wild-type strains. The organization of the two chromo-

somal loci reportedly variesamong natural populations (253). A less equivocal

instance of evolutionary change in gene copy number concerns Arabidopsis,in

which ecotypes vary inthe number of ubiquitin-encoding repeats (262). For all

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HEAT-SHOCK PROTEINS 263

of the foregoing reports, the functional signiﬁcance of intraspeciﬁc variation

awaits elucidation or direct veriﬁcation.

Hspexpressionalsoexhibitsgeneticvariationamongindividualsofaspecies;

often,thisvariationiscorrelatedwithstressresistance (248,250, 263–271). For

example, isofemale lines of Drosophila founded from a single wild population

differ more than twofold in Hsp70 expression; this variation is correlated with

thermotolerance and is heritable (180,223). Similarly, in the pathogenic fun-

gus Histoplasma, naturally temperature-insensitive strains express more hsp70

mRNA and do so at lower temperatures than in a temperature-sensitive strain

(272). In humans, ﬁbroblasts isolated from desert-dwelling Turkmen express

more Hsps and have greater thermotolerance than ﬁbroblasts from residents of

more equable climates (273); presumably, however, these peoples do not differ

in body temperature.

Given that the patterns of variation necessary for natural selection occur

within species, that selection can alter Hsp expression is not surprising. Lab-

oratory evolution at high temperatures paradoxically lowers Hsp70 expression

and inducible thermotolerance in Drosophila (19,274), and selection for re-

sistance to hyperthermic paralysis alters both the hsp68 promoter and the hsr-

omega locus in Drosophila (254,275). Additional ﬁndings relevant to natural

selection and its underlying genetic basis come from closely related species,

some so similar that they hybridize. In the ﬁsh species Poeciliopsis monacha

and P. lucida, an unusual genetic system permits the generation of hemi-

clonal lines in which the paternal genome varies against a constant mater-

nal genome. Hemiclonal thermotolerance was most strongly related to Hsc70

and only secondarily to Hsp70 levels, in a pattern consistent with straightfor-

ward Mendelian inheritance of parental genotypes and adaptation to the local

thermal environment. By contrast, the heat-shock response of interspeciﬁc hy-

brids of tomato (Lycopersicon) is not intermediate to the parental responses

(276). Non-hybridizing congeners often exhibit a correlation among the ac-

tual or inferred incidence of thermal stress in their environment, heat-shock

response, and stress tolerance. Such data are now available for diverse an-

imals (see Variation in the Stress Response Along Environmental Gradients

of Stress).

A particular problem with such species comparisons is that the interpreta-

tion of the observed patterns is readily confounded by phylogenetic and sta-

tistical issues. A more general problem with both laboratory evolution and

species comparisons is that they describe only a supposed correlation of the

heat-shock genes/proteins of interest with evolution and seldom can establish

the importance of the genes/proteins of interest to evolutionary process and

outcome (19,20). Study of free-ranging organisms (277) with hsp transgenes

(e.g. 109,278) may contribute much to resolving these problems.

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264 FEDER & HOFMANN

THE EVOLUTIONARY HISTORY OF HSPS

AND THE GENES THAT ENCODE THEM

Hsps are among the most ancient and highly conserved of all proteins. Homo-

logues of Hsps occur in every species in which they have been sought, and in

all kingdoms of living things. Thus, Hsps represent a remarkable example of

molecular “descent with modiﬁcation” at the levels of gene sequence, genomic

organization, regulation of gene expression, and protein structure and function.

So clear are the patterns of descent and modiﬁcations that they can be used to

establish the evolutionary origins and the phylogenetic afﬁnities of the major

groups of organisms.

Hsps of Archaea and Exceptional Prokaryotes

The Archaea or archaebacteria are the most extremophilic and most primi-

tive organisms. The heat-shock response of extremophilic Archaea and nonar-

chaeal extremophiles occurs at remarkably high temperatures (279), e.g. 88

◦

in Sulfolobus (279) and >100

◦

C in the hyperthermophilic species designated

ES4, a heterotrophic sulfur reducer isolated from a deep-sea hydrothermal vent

(280). The archaeal genome encodes homologues of most Hsps represented

in other prokaryotes and eukaryotes (279), as well as their consensus pro-

moter sequences (281). Notably, the archaeal Hsp60 homologues assemble

into a dual ring-like structure, termed a rosettasome or thermosome, that re-

sembles the structure that the chaperones GroEL and GroES form in bacteria

(279,282, 283). The archaeal structures have ATPase activity and can bind de-

natured proteins (282). At least some Archaea and Eubacteria differ in the

number of monomers that comprise these structures (284). Surprisingly, the

archaeal Hsp60s (e.g. TF55 of Sulfolobus) most closely resemble not a bac-

terial homologue, but the eukaryotic protein TCP1, which assembles into the

t-complex polypeptide 1 ring complex (TRiC) in the cytosol (285, 286). Pre-

viously, Hsp60 homologues were thought to be absent from the eukaryotic cy-

tosol. AgrowingbodyofevidencesuggeststhatTCP1/TRiCandGroEL/GroES

play comparable roles in their respective organisms and cellular compartments

(287–289). Meanwhile, Trent (290) has suggested that the primary function of

TF55 may be cytoskeletal, with molecular chaperoning a secondary or derived

function.

Genes encoding Hsps are present even in the smallest of genomes. These

include the genomes of mycoplasmas (291) and the nucleomorph, the vestigial

nucleusofaphototrophiceukaryoticendosymbiontincryptomonadalgae(138).

Thesection on symbiosis (see above)reviews the distributionof Hsps in various

other organelles of endosymbiotic origin. Apparently, the problem of protein

folding is ancient and ubiquitous, necessitating molecular chaperones in these

diverse cases.

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December 22, 1998 14:39 Annual Reviews AR077-10

HEAT-SHOCK PROTEINS 265

Large-Scale Evolution of hsp Genes

The extraordinarily conserved nature of hsp genes (292) has facilitated their

cloning, sequencing, and comparison in diverse organisms; their evolution is

now becoming understood in detail. Gupta and colleagues have undertaken the

most extensive surveys of hsp sequences, with a particular focus on organisms

deemedcriticaltounderstandingtherelationshipsofmajortaxa(292–297). The

interpretations resulting from these comparisons relate to hypotheses about

(a) the origin of eukaryotic cells, the eukaryotic nucleus, and endoplasmic

reticulum (292,296); (b) polyphyletic versus monophyletic origin of the major

bacterial groups (292–294); and (c) the validity of the three-domain (Archaea,

bacteria, and eukaryotes) dogma (292,294). Whereas these interpretations are

controversial, if not revolutionary, and therefore have not received universal

acceptance, theynonetheless clearly illustrate howcomparativeanalyses of hsp

genes may address fundamental issues in evolutionary history.

On a less grand scale, hsp gene families represent superb case studies of how

one or a small number of primitive genes can diversify to encode a suite of

compartment- and function-speciﬁc proteins. One of many examples is dnaK,

a single gene in Archaea and bacteria that has become the complex multi-

genehsp70 familiesofSaccharomyces(298), Drosophila (253,299), and Homo

(300). Another example concerns the small Hsps, which evolution recruited

to become a major component of the lens of the eye: alpha crystallin (301).

A growing body of work examines the discrete evolutionary events by which

thesechangesmay have occurred, includinggeneduplication/conversionevents

(302), retrotransposition, horizontal exchange of genomes, and others. New

technologies promise to advance this work exponentially.

Discrete Examinations of Molecular Evolution

Ideally,a complete study of theevolutionary physiologyofHspsmight examine

how the following co-evolve as populations or how closely related species

enter environments in which they face novel stresses: sequence (both coding

and non-coding) of the gene(s) for a particular Hsp, regulation of hsp gene

expression, the role and importance of the Hsp in stress resistance, and the

intensities and durations of stress that the populations and species actually face.

Much of the evolutionary physiological investigation of Hsps fails to attain this

admittedly ambitious goal for one or more reasons: (a) The species under study

aretoodistantlyrelatedtoreconstructthefunctional,environmental,andgenetic

events during their divergence; (b) molecular biology, manipulative genetics,

physiology, and environmental assessment are not all possible for the species

in question; or (c) the breadth of the techniques and approaches necessary to

perform such research is too daunting for a single research program. Two case

studies exemplify both how this goal could be approached and how far the ﬁeld

has yet to go to attain it.

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December 22, 1998 14:39 Annual Reviews AR077-10

266 FEDER & HOFMANN

The coelenterate Hydra oligactis and several of its congeners are the only

multicellular eukaryotes reported not to express Hsps in response to heat shock

and other stresses. Other congeners (e.g. Hydra attenuata and H. magnipapil-

lata) have a well-developed stress response; these and other data for puta-

tive ancestors of Hydra suggest an evolutionary loss of Hsp expression in

H. oligactis (95, 96). Physiologically and ecologically, H. oligactis is deﬁ-

cient in inducible stress tolerance and disappears from certain habitats in na-

ture during periods of stress (95). Subsequent work suggests that, at least

for Hsp70, the loss has occurred due to mutations that affect the stability of

hsp70 mRNA, as H. oligactis hasan hsp70 gene and expresses a heat-inducible

hsp70 mRNAin quantities similar to that in the heat-tolerant H. magnipapillata

(96).

Dipteran insects and their ancestors have undergone an evolutionary prolif-

eration of hsp70 genes. Mosquitoes and Drosophila share a distinctly arranged

duplication of the inducible hsp70 gene (303), suggesting that this prolifer-

ation predates the original diversiﬁcation of the Diptera. Within the genus

Drosophila, all groups other than the melanogaster subgroup of species ap-

parently retain the primitive copy number of two (108,304,305). Within the

melanogaster subgroup, all species examined to date have four copies except

for D. melanogaster (253), which has at least ﬁve hsp70 copies in its haploid

genome(seeMicroevolutionaryVariationinHsps). Curiously,D.melanogaster

expresses no Hsp100 family members, which are critical for thermotolerance

in other organisms (204,306). The proliferation of hsp70 copies is correlated

with the ecological and biogeographic distribution of Drosophila species (19).

Whereas most Drosophila species have small geographic ranges or narrow

ecological niches, two of the melanogaster subgroup species (simulans and

melanogaster) have cosmopolitan distributions, and a third (yakuba) is eco-

logically diverse throughout sub-Saharan Africa.

CONCLUSION

Ecological and evolutionary physiological analysis of heat-shock proteins may

be nearing the end of its initial descriptive phase. Although accounts of spec-

tacular levels of Hsp-mediated stress resistance and exceptional consequences

of Hsp expression will continue to be newsworthy, the major patterns of Hsp

expression in multicellular eukaryotes are becoming so obvious that additional

descriptive work is becoming increasingly difﬁcult to justify. Clearly, how-

ever, major questions remain unanswered. How the activities of Hsps at the

molecularlevel culminate in organismalstress tolerance and how thehsp genes,

their regulation, the function of the proteins they encode, and the environments

faced by the organisms in which they occur all co-evolve are but two of the

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December 22, 1998 14:39 Annual Reviews AR077-10

HEAT-SHOCK PROTEINS 267

unresolved issues reviewed here. The perspective of evolutionary physiology

can make signiﬁcant contributions to the resolution of these and other issues.

By placing results in actual environmental contexts, by assessing phenotypes

of Hsps in the context of whole multicellular organisms, and by characterizing

extant and historical variation in Hsps in natural populations and taxa, evolu-

tionary physiologists can complement and extenda spectacular area of research

that has been largely restricted to the molecular/cellular levels in the laboratory.

By the same token, insights and techniques that laboratory-based investigators

provide promise to continue to revolutionize the ecological and evolutionary

study of Hsps. These approaches are both logical partners and necessary com-

plements to one another (22,307). Our understanding of Hsps has much to gain

from the continued if not expanded synergy of these approaches.

CKNOWLEDGMENTS

We thank BR Bettencourt, K Chavez, UT D’OBrador, AP Nguyen, J Meredith-

Patla, and AC Whitmer for bibliographic assistance and/or editorial advice,

and Susan Lindquist for founding the bibliographic database that made this re-

view possible. Research was supported by National Science Foundation grants

97-23298 and 97-23063. Finally and most importantly, we beg the indulgence

of numerous investigators whom space limitations precluded us from citing

directly here; their contributions have made the ﬁeld what it is today. We urge

allreaderscontemplatingresearch inthisareatoscan thecompletebibliography

(13) available online at http://www.AnnualReviews.org.

Visit the Annual Reviews home page at

http://www.AnnualReviews.org

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Environmental specificity of karst cave habitats evidenced by diverse symbiotic bacteria in Opiliones

Article

Full-text available

May 2024

Background Karst caves serve as natural laboratories, providing organisms with extreme and constant conditions that promote isolation, resulting in a genetic relationship and living environment that is significantly different from those outside the cave. However, research on cave creatures, especially Opiliones, remains scarce, with most studies focused on water, soil, and cave sediments. Results The structure of symbiotic bacteria in different caves were compared, revealing significant differences. Based on the alpha and beta diversity, symbiotic bacteria abundance and diversity in the cave were similar, but the structure of symbiotic bacteria differed inside and outside the cave. Microorganisms in the cave play an important role in material cycling and energy flow, particularly in the nitrogen cycle. Although microbial diversity varies inside and outside the cave, Opiliones in Beijing caves and Hainan Island exhibited a strong similarity, indicating that the two environments share commonalities. Conclusions The karst cave environment possesses high microbial diversity and there are noticeable differences among different caves. Different habitats lead to significant differences in the symbiotic bacteria in Opiliones inside and outside the cave, and cave microorganisms have made efforts to adapt to extreme environments. The similarity in symbiotic bacteria community structure suggests a potential similarity in host environments, providing an explanation for the appearance of Sinonychia martensi in caves in the north.

Genome-wide identification, classification and expression analysis of the heat shock transcription factor family in Garlic (Allium sativum L.)

Article

Full-text available

May 2024
BMC PLANT BIOL

Background The heat shock transcription factor (HSF) plays a crucial role in the regulatory network by coordinating responses to heat stress as well as other stress signaling pathways. Despite extensive studies on HSF functions in various plant species, our understanding of this gene family in garlic, an important crop with nutritional and medicinal value, remains limited. In this study, we conducted a comprehensive investigation of the entire garlic genome to elucidate the characteristics of the AsHSF gene family. Results In this study, we identified a total of 17 AsHSF transcription factors. Phylogenetic analysis classified these transcription factors into three subfamilies: Class A (9 members), Class B (6 members), and Class C (2 members). Each subfamily was characterized by shared gene structures and conserved motifs. The evolutionary features of the AsHSF genes were investigated through a comprehensive analysis of chromosome location, conserved protein motifs, and gene duplication events. These findings suggested that the evolution of AsHSF genes is likely driven by both tandem and segmental duplication events. Moreover, the nucleotide diversity of the AsHSF genes decreased by only 0.0002% from wild garlic to local garlic, indicating a slight genetic bottleneck experienced by this gene family during domestication. Furthermore, the analysis of cis-acting elements in the promoters of AsHSF genes indicated their crucial roles in plant growth, development, and stress responses. qRT-PCR analysis, co-expression analysis, and protein interaction prediction collectively highlighted the significance of Asa6G04911. Subsequent experimental investigations using yeast two-hybridization and yeast induction experiments confirmed its interaction with HSP70/90, reinforcing its significance in heat stress. Conclusions This study is the first to unravel and analyze the AsHSF genes in garlic, thereby opening up new avenues for understanding their functions. The insights gained from this research provide a valuable resource for future investigations, particularly in the functional analysis of AsHSF genes.

Screening and Identification of the Biomarkers Applied for the Evaluation of Acute and Chronic Thermal Tolerance Ability in Largemouth Bass (Micropterus salmoides)

Article

Full-text available

May 2024

Affected by the continuously rising temperature, thermal stress leads to a delinked growth rate and resistance to stress in cultured largemouth bass (Micropterus salmoides, LMB) in China. Identification of LMB with better thermal resistance will benefit the breeding of new varieties. However, there has been limited reporting on the evaluation to identify LMB with better thermal resistance. LMB consists of the northern LMB (Micropterus salmoides salmoides, NLMB) and the Florida LMB (Micropterus salmoides floridanus, FLMB). Due to their different geographical distributions, it has been suggested that FLMB exhibit better thermal resistance compared to NLMB. In this study, NLMB and FLMB were subjected to thermal stress for 3 h (acute) and 60 d (chronic) at 33 °C, respectively. Subsequently, the variations of 12 candidate biomarkers between NLMB and FLMB were analyzed. Exposure to acute thermal stress significantly increased plasma cortisol, blood glucose, and lactate levels; activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), glucose kinase (GK), pyruvate kinase (PK), lactate dehydrogenase (LDH), and glucose 6 phosphatase (G6Pase); and the expressions of hsp70 and hsp90 in both NLMB and FLMB (p < 0.05). Compared to NLMB, FLMB exhibited a lower plasma cortisol level and a higher expression of hsp90 under acute thermal stress (p < 0.05). Exposure to chronic thermal stress significantly increased plasma cortisol and blood glucose levels, as well as activities of GK, PK, LDH, and G6Pase, as well as expressions of hsp70 and hsp90 in both NLMB and FLMB (p < 0.05). Additionally, FLMB showed a lower expression of hsp70 compared to NLMB (p < 0.05). In conclusion, our results showed that LMB with lower plasma cortisol level and higher expression of hsp90 under acute thermal stress, as well as lower expression of hsp70 under chronic thermal stress were suggested to have better thermal resistance. Our study provides valuable information for identifying and breeding LMB varieties with better thermal resistance in the future.

Transcriptomic analysis of thermotolerant Artemia franciscana populations shows that thermal adaptation affects expression and regulation of metabolism-, stress-, and immune-related genes

Preprint

Full-text available

Apr 2024

Brine shrimp Artemia franciscana is a commercially important species in aquaculture and is well adapted to harsh environmental conditions. In this study, an A. franciscana population selectively bred for induced thermotolerance over 12 generations (TF12) was subjected to transcriptomic analysis relative to the non-selective population (CF12) to determine the effect of selective breeding for induced thermotolerance (SITT). The transcriptomic response of CF12 to non-lethal heat stress (NLHS) from ITT within one generation was also investigated. A total of 232 and 218 differentially expressed genes (DEGs) were upregulated and downregulated in TF12, respectively, whereas fewer DEGs were upregulated (114) and downregulated (180) in CF12 exposed to NLHS, suggesting a more complex mechanism of thermal adaptation in SITT than in ITT. The TF12 population exhibited a reduction in immune processes as indicated by the downregulation of several pattern-recognition receptors. Conversely, stress protein genes such as those of heat shock proteins (HSPs) and of antioxidant enzymes and genes involved in carbohydrate metabolism, were highly upregulated. ITT downregulated immune-related and growth-related genes, whereas genes involved in energy production and electron carrier activity were upregulated. Our findings suggest possible immunological and physiological mechanisms and molecular pathways involved in adaptation of A. franciscana to thermal stress.

Temperature Effects on Expression Levels of hsp Genes in Eggs and Second-Stage Juveniles of Meloidogyne hapla Chitwood, 1949

Article

Full-text available

Apr 2024
INT J MOL SCI

Meloidogyne hapla is one of the most important nematode pathogens. It is a sedentary, biotrophic parasite of plants that overwinters in the soil or in diseased roots. The development of M. hapla is temperature dependent. Numerous studies have been performed on the effect of temperature on the development of M. hapla, but only a few of them analyzed the heat shock protein (hsp) genes. The aim of the study was to perform expression profiling of eight hsp genes (Mh-hsp90, Mh-hsp1, Mh-hsp4, Mh-hsp6, Mh-hsp60, Mh-dnj19, Mh-hsp43, and Mh-hsp12.2) at two development stages of M. hapla, i.e., in eggs and second-stage juveniles (J2). The eggs and J2 were incubated under cold stress (5 °C), heat stress (35 °C, 40 °C), and non-stress (10 °C, 20 °C, and 30 °C) conditions. Expression profiling was performed by qPCR. It was demonstrated that only two genes, Mh-hsp60 and Mh-dnj19, have been upregulated by heat and cold stress at both development stages. Heat stress upregulated the expression of more hsp genes than cold stress did. The level of upregulation of most hsp genes was more marked in J2 than in eggs. The obtained results suggest that the Mh-hsp90 and Mh-hsp1 genes can be used as bioindicators of environmental impacts on nematodes of the Meloidogyne genus.

Osmoregulation and HSP70 abundance in freshwater catfish Rhamdia quelen under acute salt exposure

Article

Full-text available

May 2024
ENVIRON BIOL FISH

Understanding how freshwater species respond to changes in salinity is essential for comprehending their distribution and ecological niches. We investigated the osmoregulatory mechanisms of the freshwater catfish Rhamdia quelen, which could justify occasional incursions and residence in brackish waters and their resistance to salt treatments in aquaculture. Specimens were exposed to freshwater (control) and dilute seawater (15 ‰) for 6 h. It was measured: plasma osmolality and Na⁺, K⁺, and Cl⁻ concentrations; gills and kidneys Na⁺/K⁺-ATPase (NKA), V(H⁺)-ATPase (VAT), and carbonic anhydrase (CA) enzymes activities; gills enzymatic immunolocalization and Heat Shock Protein (HSP70) abundance. Our results showed that R. quelen presented hypoosmotic/ionic regulation in 15 ‰. However, there was no significant effect of the increased salinity on enzymatic activities in the gills and kidneys, or in the abundance of HSP70. All enzymatic activities, except for CA, were higher in the kidneys compared to the gills. The immunolocalization of NKA and VAT was observed in ionocytes of the interlamellar region of the gills, and the pavement cells, while CA was detected in both ionocytes and red blood cells. The lack of change in the abundance of HSP70 may be attributed to the protein’s high constitutive abundance in the gill cells. The results indicate a complex regulatory network in response to high salinity, showing that brief periods of salty water exposure could be enough for the species to move or spread in brackish waters or survive aquaculture disease treatments.

Multigenerational Effect of Heat Stress on the Drosophila melanogaster Sperm Proteome

Article

May 2024

Phosphorylation of 399S at CsHsp70 of Cymbidium sinense is essential to maintain chlorophyll stability

Article

May 2024
PLANT PHYSIOL BIOCH

A systematic review of approaches to assess fish health responses to anthropogenic threats in freshwater ecosystems

Article

May 2024

Anthropogenic threats such as water infrastructure, land-use changes, overexploitation of fishes and other biological resources, invasive species and climate change present formidable challenges to freshwater biodiversity. Historically, management of fish and fishery species has largely been based on studies of population- and community-level dynamics; however, the emerging field of conservation physiology promotes the assessment of individual fish health as a key management tool. Fish health is highly sensitive to environmental disturbances and is also a fundamental driver of fitness, with implications for population dynamics such as recruitment and resilience. However, the mechanistic links between particular anthropogenic disturbances and changes in fish health, or impact pathways, are diverse and complex. The diversity of ways in which fish health can be measured also presents a challenge for researchers deciding on methods to employ in studies seeking to understand the impact of these threats. In this review, we aim to provide an understanding of the pathway through which anthropogenic threats in freshwater ecosystems impact fish health and the ways in which fish health components impacted by anthropogenic threats can be assessed. We employ a quantitative systematic approach to a corpus of papers related to fish health in freshwater and utilize a framework that summarizes the impact pathway of anthropogenic threats through environmental alterations and impact mechanisms that cause a response in fish health. We found that land-use changes were the most prolific anthropogenic threat, with a range of different health metrics being suitable for assessing the impact of this threat. Almost all anthropogenic threats impacted fish health through two or more impact pathways. A robust understanding of the impact pathways of anthropogenic threats and the fish health metrics that are sensitive to these threats is crucial for fisheries managers seeking to undertake targeted management of freshwater ecosystems.

EGCG alleviates heat-stress-induced fat deposition by targeting HSP70 through activation of AMPK-SIRT1-PGC-1α in porcine subcutaneous preadipocytes

Article

May 2024
BIOCHEM PHARMACOL

Chaperonin filaments: The archaeal cytoskeleton?

Article

Full-text available

May 1997

Chaperonins are high molecular mass double-ring structures composed of 60-kDa protein subunits. In the hyperthermophilic archaeon Sulfolobus shibatae the two chaperonin proteins represent approximate to 4% of its total protein and have a combined intracellular concentration of >30 mg/ml. At concentrations greater than or equal to 0.5 mg/ml purified chaperonins form filaments in the presence of Mg2+ and nucleotides. Filament formation requires nucleotide binding (not hydrolysis), and occurs at physiological temperatures in biologically relevant buffers, including a buffer made from cell extracts. These observations suggest that chaperonin filaments may exist in vivo and the estimated 4600 chaperonins per cell suggest that such filaments could form an extensive cytostructure. We observed filamentous structures in unfixed, uranyl-acetate-stained S. shibatae cells, which resemble the chaperonin filaments in size and appearance. ImmunoGold (Janssen) labeling using chaperonin antibodies indicated that many chaperonins are associated with insoluble cellular structures and these structures appear to be filamentous in some areas, although they could not be uranyl-acetate-stained. The existence of chaperonin filaments in vivo suggests a mechanism whereby their protein-folding activities can be regulated. More generally, the filaments themselves may play a cytoskeletal role in Archaea.

Guidebook to Molecular Chaperones and Protein-Folding Catalysts

Article

Nov 1997

Mary-Jane Gething

The precise shape of a protein is a crucial factor in its function. How do proteins become folded into the right conformation? Molecular chaperones and protein folding catalysts bind to developing polypeptides in the cytoplasm and ensure correct folding and transport. This Guidebook catalogues the latest information on nearly 200 of these molecules, including the important class of heat shock proteins; each entry is written by leading researchers in the field.

Heat shock stress is deleterious to CNS cultured neurons microinjected with anti-HSP70 antibodies

Article

Jan 1989

N Khan

Ecological and evolutionary physiology of stress proteins and the stress response: the Drosophila melanogaster model

Chapter

Oct 1996

M.E. Feder

Environmental temperature varies in time and space on timescales ranging from a few hours to long-term climate change. Organisms are therefore continually challenged to regulate and maintain functional capacities as their thermal environment changes. This volume brings together many of the leading workers in thermal biology, with backgrounds spanning the disciplines of molecular biology, cell biology, physiology, zoology, ecology and evolutionary biology, to discuss the responses of a wide range of species to temperature change at all scales of organization, ranging through the molecular, cellular, organismal, population and ecosystem levels. The volume provides an important and comprehensive contribution to the study of temperature adaptation, which, given the concern about global climate change, will provide much to interest a wide range of biologists.

Biophysical Ecology

Article

Jan 1980

David M. Gates

The objective of this book is to make analytical methods available to students of ecology. The text deals with concepts of energy exchange, gas exchange, and chemical kinetics involving the interactions of plants and animals with their environments. The first four chapters are designed to show the applications of biophysical ecology in a preliminary, sim plified manner. Chapters 5-10, treating the topics of radiation, convec tion, conduction, and evaporation, are concerned with the physical environment. The spectral properties of radiation and matter are thoroughly described, as well as the geometrical, instantaneous, daily, and annual amounts of both shortwave and longwave radiation. Later chapters give the more elaborate analytical methods necessary for the study of photosynthesis in plants and energy budgets in animals. The final chapter describes the temperature responses of plants and animals. The discipline of biophysical ecology is rapidly growing, and some important topics and references are not included due to limitations of space, cost, and time. The methodology of some aspects of ecology is illustrated by the subject matter of this book. It is hoped that future students of the subject will carry it far beyond its present status. Ideas for advancing the subject matter of biophysical ecology exceed individual capacities for effort, and even today, many investigators in ecology are studying subjects for which they are inadequately prepared. The potential of modern science, in the minds and hands of skilled investigators, to of the interactions of organisms with their advance our understanding environment is enormous.

TRANSGENIC hsp 16-lacZ STRAINS OF THE SOIL NEMATODE CAENORHABDITIS ELEGANS AS BIOLOGICAL MONITORS OF ENVIRONMENTAL STRESS

Article

Jan 1994

Heat shock protein gene expression in response to physiologic stress and aging

Article

Jan 1994

Heat shock proteins and stress tolerance

Article

Jan 1994

Heat shock proteins and stress tolerance

Article

Jan 1994

Reduced protein denaturation in thermotolerant cells by elevated levels of HSP70

Article

Jan 1996

We describe a novel approach to evaluate quantitatively the amounts of denatured proteins in cells upon heat exposure. A thiol compound, diamide [azodicarboxylic acid bis (dimethylamide)] causes protein cross-linking with exposed sulfhydryl residues of denatured proteins. Since denatured proteins expose normally well-hidden sulfhydryl groups, these will be preferentially cross-linked by diamide. Thus diamide acts to 'trap' denatured proteins. We observed that protein aggregates (high molecular weight protein aggregates, HMA) appeared on SDS-polyacrylamide gels run under non-reducing conditions and that the amount of HMA can be quantified by scanning the gels using a gas flow counter. Heating cells followed by a fixed dose of diamide exposure resulted in HMA increases in a heat-dose dependent manner, demonstrating that the quantitation of HMA could ve as a measure of heat-denatured proteins. We compared thermotolerant and nontolerant cells and found decreased HMA in tolerant cells upon heat treatment. As an attempt to examine the kinetics of protein renaturation (or 'repair'), we measured the amounts of aggregates formed by the addition of diamide at various times after heat shock. Such experiments demonstrate an equally rapid disappearance of HMA in previously unheated and in thermotolerant cells. Levels of HMA in tolerant cells increased significantly after electroporation of HSP70 specific mAbs, suggesting an involvement of HSP70 in reducing HMA levels in thermotolerant cells upon heat exposure. Immunoprecipitation studies using anti-HSP70 antibody indicated an association of HSP70 with heat-denatured proteins. Our results suggest that heat induces protein denaturation, and that elevated level of HSP70 present in thermotolerant cells protects them by reducing the level of protein denaturation rather than by facilitating the 'repair' (or degradation) process.

Heat-shock proteins, molecular chaperones, and the stress response: Evolutionary and Ecological Physiology

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