Hindawi Publishing Corporation
International Journal of Microbiology
Volume 2009, Article ID 525491, 15 pages
KelsiL.Andersonand PaulM. Dunman
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-6495, USA
Correspondence should be addressed to Paul M. Dunman, email@example.com
Received 22 August 2008; Accepted 14 November 2008
Recommended by Arsenio M. Fialho
The regulation of mRNA turnover is a recently appreciated phenomenon by which bacteria modulate gene expression. This review
outlines the mechanisms by which three major classes of bacterial trans-acting factors, ribonucleases (RNases), RNA binding
proteins, and small noncoding RNAs (sRNA), regulate the transcript stability and protein production of target genes. Because the
mechanisms of RNA decay and maturation are best characterized in Escherichia coli, the majority of this review will focus on how
these factors modulate mRNA stability in this organism. However, we also address the effects of RNases, RNA binding proteins,
sRNAs on mRNA turnover, and gene expression in Bacillus subtilis, which has served as a model for studying RNA processing
in gram-positive organisms. We conclude by discussing emerging studies on the role modulating mRNA stability has on gene
expression in the important human pathogen Staphylococcus aureus.
Copyright © 2009 K. L. Anderson and P. M. Dunman. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
RNA steady-state levels are a function of both transcript
synthesis and decay. Nonetheless, studies of prokaryotic
mRNA regulation have historically interpreted changes in
mRNA titers on the basis of transcript synthesis alone. It
has been recently recognized that this is likely an oversim-
plification; the modulation of mRNA decay also profoundly
affects mRNA titers and, consequently, protein production.
A growing body of literature suggests that the regulation of
many, if not all, bacterial species.
As a precursor to reviewing the factors that regulate
bacterial mRNA turnover, we provide examples of how
alterations in transcript degradation mediate bacterial adap-
tation to stress conditions, growth phase transition, and
pathogenesis. This is designed to provide the reader with
an appreciation of the magnitude of biological responses
that are regulated at the level of mRNA turnover and
introduce three classes of molecules that govern these
changes: ribonucleases (RNases), RNA binding proteins, and
noncoding RNAs (sRNA).
Bacteria have developed highly orchestrated responses
to environmental stress which, when elicited, alter the
cellular physiology in a manner that enhances survival.
Recent reports indicate that regulated changes in mRNA
turnover play a vital role in bacterial stress adaptation
protein CspA, which resolves low temperature mediated
mRNA secondary structures that would otherwise impede
translation, reaches more than 10% of the total cellular
protein concentration during cold shock conditions [2–
4]. Upon temperature downshift, increased cspA mRNA
stability, as opposed to changes in transcript synthesis,
primarily accounts for the increase in CspA production [5–
7]. This change in cspA mRNA stability reflects alterations
in the transcript’s vulnerability to digestion by the endori-
bonuclease RNase E . As described below, regulating a
target transcript’s accessibility to ribonucleases is a common
means of modulating mRNA turnover. Stress-responsive
changes in mRNA turnover are not restricted to E. coli. The
Vibrio angustum response to nutrient deprivation and the
Klebsiella pneumoniae nitrogen fixation system are mediated
by alterations in mRNA degradation [1, 9, 10]. Similarly,
2 International Journal of Microbiology
stringent, cold shock, and heat shock conditions alter
Staphylococcus aureus mRNA turnover .
In addition to stress adaptation, the modulation of
mRNA turnover may play a role in regulating bacterial
cell growth phase processes. Indeed, the transition from
log to stationary phase growth stabilizes many transcripts
within the human pathogens S. aureus and Streptococcus
pyogenes (Anderson & Dunman, unpublished; ). While
it remains to be seen what, if any, biological significance
growth phase-induced alterations in mRNA turnover might
have on these organisms, the effects of growth dependent
changes in transcript stability are well characterized for
other bacterial species. For instance, stability of the E. coli
outer membrane protein A (ompA) transcript is inversely
correlated with growth rate [13–15]. As described further
below, ribonuclease E, the RNA binding protein Hfq, and a
noncoding RNA molecule MicA/SraD coordinately regulate
ompA mRNA stability which, in turn, influences OmpA
The modulation of mRNA turnover also mediates bacte-
rial virulence factor production. Although several examples
exist, perhaps the best includes the effector of the E. coli
carbon storage regulatory system, CsrA. CsrA binds target
transcripts and alters the mRNA stability and, consequently,
translationofproteinsinvolved in carbonutilization, biofilm
formation, and motility [16–18]. Interestingly, the effects
of CsrA binding are transcript specific. For instance, bind-
ing stabilizes the flhDC transcript and leads to increased
production of proteins involved in flagellum biosynthesis.
This increase in protein production may result from either
activation of translation or protection of the message from
ribonuclease attack . Conversely, CsrA binding to the
pgaABCD leader sequence results in inhibition of ribosome
binding, transcript destabilization, and, consequently, loss
of polysaccharide adhesion (PGA) production which is
required for biofilm formation and plays a role in patho-
genesis . CsrA homologues influence virulence factor
production in Salmonella typhimurium, Erwinia carotovara
ssp. carotovora, and Pseudomonas aeruginosa [19–21]. Recent
reports have also linked S. aureus’ regulation of virulence
factor mRNA turnover to corresponding changes in viru-
lence factor protein production. For instance, a product of
the pleiotropic regulatory locus, sarA, appears to stabilize the
mRNA and repress production of two S. aureus virulence
factors: protein A (spa) and collagen adhesion protein (cna)
. Likewise, Romby et al. have shown that a sRNA-like
molecule, RNAIII, and endoribonuclease III modulate the
mRNA turnover of a subset of the organism’s virulence
factors [23, 24]. Although less characterized, production of
other S. aureus virulence factors, fibronectin binding protein
B (fnbB) and coagulase (coa), is also mediated by mRNA
Admittedly, studies designed to assess the effects of
mRNA turnover on protein production are in their infancy.
Nonetheless, the aforementioned examples establish that
regulated transcript degradation, in part, modulates many
biological processes. Although the molecular components
that govern the stabilization/destabilization of individual
transcripts differ, pioneering work from the Deutscher,
Condon, Romeo, and Gottesman laboratories indicates that
they can be broadly categorized as ribonucleases (and aux-
iliary factors), RNA binding proteins, and small noncoding
RNAs. In this review, we will overview these three major
classes of trans-acting RNA turnover regulatory molecules
in the prototypic gram-negative and gram-positive bacterial
species, E. coli and Bacillus subtilis, respectively. Finally, we
describe recent S. aureus RNA turnover studies and provide
an emerging view of how these factors may contribute to the
organism’s ability to coordinately regulate virulence factors
and cause disease.
2.Control ofEscherichia coli Messenger
2.1. Ribonucleases. Ribonucleases (RNases) are a class of
enzymes that are responsible for RNA degradation and
processing. These enzymes are classified as endo- and 3?→
5?exoribonucleases (Table 1). In addition, an RNase with
unique 5?→ 3?exoribonucleolytic activity has recently been
described in B. subtilis [26, 27]. At least two ribonucleases
are components of a holoenzyme complex, the RNA degra-
dosome, which catalyzes bulk E. coli mRNA degradation.
In addition to the RNA degradosome, E. coli produces
other endo- and exoribonucleases, many of which are largely
considered to be involved in rRNA and tRNA maturation
rather than bulk mRNA decay. A subset of these enzymes
contribute to the decay of individual mRNA species, whereas
others have not yet, or have only circumstantially, been
linked to mRNA degradation. It is likely that as each of these
ribonucleases becomes better characterized, many will be
found to contribute to mRNA decay. In the pages that follow,
we describe components of the E. coli RNA degradosome
and other RNases that mediate processing/degradation of
targeted bacterial mRNA species. Moreover, we discuss
and other bacterial RNases is modulated as a means of
regulating mRNA levels during cellular proliferation and
2.1.1. The Degradosome. The E. coli degradosome is com-
posed of at least four proteins: ribonuclease E (RNase E),
polynucleotide phosphorylase (PNPase), RhlB RNA helicase,
a model for mRNA decay has been proposed in which the
degradosome loads and scans an mRNA molecule for an
RNase E cleavage site, A/U-rich sequences usually proceeded
by a stem-loop structure in 5?monophosphorylated tran-
scripts, in the 5?
→ 3?direction [29, 30]. Once this site
is encountered, RNase E catalyzes an initial endoribonucle-
olytic event and then continues to cleave the transcript at
additional downstream target sites. Fragmentation products
are subsequently degraded by the 3?
clease, PNPase . RhlB RNA helicase-mediated removal
of mRNA secondary structures is thought to facilitate
PNPase degradation , whereas enolase may participate
in bulk degradation of metabolic enzyme transcripts [28,
International Journal of Microbiology3
Table 1: E. coli, B. subtilis, and S. aureus ribonucleases.
Endoribonucleases ExoribonucleasesToxin-mediated ribonucleases
E. coli B. subtilis
B. subtilisE. coli
S. aureus S. aureus
E. coli B. subtilis
rnlA S. aureus
∗Gene symbols of putative RNases in S. aureus.
†S. aureus N315 loci of genes homologous to B. subtilis RNases.
Figure 1: Degradosome-mediated RNA decay. The E. coli degrado-
some is composed of at least four subunits: RNase E, PNPase, RhlB
helicase, and enolase. The initial RNA cleavage event is catalyzed
by the 5?→ 3?endoribonuclease RNase E (large cut-out circle)
which loads onto a transcript and scans for downstream cleavage
sites: A/U rich regions proceeded by stem-loop structures in 5?
monophosphorylated transcripts. The 3?
PNPase (small cut-out circle) catalyzes cleavage of RNase E-
generated decay intermediates. Otherwise inhibitory secondary
structures to PNPase-mediated degradation are resolved by RhlB
helicase (cross). The role of enolase (hexagon) in mRNA decay is
not well characterized.
Components of the degradosome are localized to the
cell membrane and are organized into helical filaments that
coil around the length of the cell [34–36]. This organization
may provide a means for the apparatus to interact with
other cell membrane-associated macromolecular complexes
[35, 36]. Indeed, the degradosome appears to be a dynamic
organelle; during cold shock conditions, the complex’s RNA
CsdA . The cold shock protein CspE also interacts
with degradosome-associated ribonucleases . Further,
the heat shock proteins GroEL and DnaK have been shown
to be associated with the degradosome . It remains to
be seen whether these auxiliary factors affect global mRNA
decay. Rather, it seems likely that they may redirect the
efficiency with which the degradosome catalyzes turnover of
individual or subsets of mRNA species. This would provide
an efficient means of modulating protein production in a
manner that allows cells to quickly adapt to otherwise delete-
rious conditions. It is very likely that as the field matures,
additional degradosome auxiliary factors will be identified
and characterized. As a first step toward understanding
how the holoenzyme’s function can be altered in response
to endogenous and exogenous cues, one must first appre-
ciate the components of the “native” RNA degradosome
RNase E [rne; 118 kilodalton (kDa)] is an essential
endoribonuclease that organizes other components of the E.
coli degradosome and initiates bulk RNA decay . The
C-terminal region of RNase E acts, in part, as a scaffold
for assembly of the other major degradosome components
[39–41]. The protein’s internal domain is required for cell
membrane association, whereas its N-terminus is required
for cell viability and RNA cleavage [31, 41, 42]. In addition
to its role in mediating bulk mRNA degradation, RNase E is
4 International Journal of Microbiology
involved in the maturation of both ribosomal and transfer
RNA molecules [43–46].
Because RNase E is responsible for many RNA decay
and maturation processes, it stands to reason that it must
be tightly regulated. Indeed, RNase E autoregulates itself by
controlling the cleavage of its cognate mRNA [47, 48]. When
RNase E activity is low or when substrate transcripts reach
increased RNase E production . As substrate molecules
aredepleted, rne mRNAdegradation andproteinproduction
return to basal levels . As discussed further below,
trans-acting factors such as noncoding RNAs, RNA binding
proteins, and the translation apparatus frequently indirectly
affect RNase E function by altering a target transcript’s
accessibility to the enzyme.
During normal laboratory growth conditions, polynu-
cleotide phosphorylase (PNPase; pnp; 80kDa) functions as
a nonessential, 3?→ 5?exoribonuclease component of the
degradosome . Although other cellular exoribonucleases
can rescue a loss of PNPase activity, they do so with
reduced efficiency; pnp-mutants produce transcripts with
mildly increased steady-state levels . As opposed to
normal growth conditions, PNPase is essential for survival
at low temperatures (<20◦C). Following cold acclimation,
the enzyme is required for degradation of low temperature
stabilized transcripts whose accumulation would other-
wise be lethal . The temperature mediated change
in cellular PNPase dependence suggests that ribonuclease
functions/importance changes in response to internal and/or
external stimuli. As the field matures, it is likely that
this phenomenon will be observed for additional RNases.
In addition to its role in degradosome-mediated RNA
degradation and cold shock adaptation, PNPase may also
participate in 3?polyadenylation of mRNA [50, 53, 54].
Although not ribonucleases, RhlB helicase and eno-
lase are integral members of the E. coli degradosome.
RhlB (rhlB; 47kDa) is a DEAD box RNA helicase that
unwinds RNA secondary structures via energy generated by
ATP hydrolysis . Presumably, RhlB facilitates PNPase-
mediated digestion of RNase E-generated fragments .
The glycolytic enzyme enolase (eno; 46kDa) is an abundant
E. coli protein; ∼10% of all cellular enolase is associated
as part of the degradosome has not been elucidated, some
studies have indicated a possible role for enolase in bulk
mRNA turnover of some metabolic enzymes [28, 33].
2.1.2. Endoribonucleases. RNase III (rnc; 26kDa) is an
endoribonuclease that cleaves double-stranded RNA .
Although the enzyme is best known for its role in rRNA mat-
uration, RNase III also regulates the mRNA decay of a subset
of RNA species, including pnp, which contain a 5?stem
loop structure. Other noted RNase III substrates include
the intergenic regions of rplL-rpoB , rpsO-pnp [58, 59],
dicA-dicF-dicB , and metY-nusA  transcripts. In
addition to its role in degrading target RNA molecules,
RNase III has been shown to bind the 5?untranslated
region (UTR) of bacteriophage λ cIII transcripts. Binding
alters the mRNA conformation and alleviates an otherwise
translation-inhibitory structure [62, 63]. Thus, RNase III
has at least two post-transcriptional regulatory mechanisms
which are facilitated by its RNA binding and/or RNA
RNase P is a holoenzyme consisting of a ribozyme
(rnpB; 377 nucleotides) and at least one protein subunit,
RnpA (rnpA; 14kDa) . The major function of the
ribonucleoprotein complex has been considered to be cat-
alyzing cleavage of the 5?leader sequence of precursor
tRNAs [65, 66]. It is well established that the ribozyme is
the catalytic unit, whereas the protein component aids in
substrate recognition [65, 67]. Interestingly, although both
the RNase P ribozyme and protein subunits are essential in
tRNA processing . RNase P has also been implicated in
the cleavage of intergenic regions of polycistronic mRNA
molecules and the degradation of guide RNAs [68, 69].
Thus, RNase P may facilitate both tRNA maturation and
degradation of subsets of mRNA species during distinct
conditions. Indeed, RNase P activity is regulated in response
to nutrient limitation [70, 71].
Two ribonuclease H genes exist within E. coli. Although
they have similar functions, they share limited sequence
similarity. RNase HI (rnhA; 18kDa) was the first to be
identified. The enzyme degrades the RNA component of
beendetermined forRNaseHI.However,potential functions
havebeenproposed including theremovalOkazakifragment
primers as well as primers at sites other than the vegetative
origin of replication [72, 73]. The second E. coli ribonuclease
H gene, RNase HII (rnhB; 23kDa), also degrades the RNA
component of RNA/DNA hybrid molecules [74, 75]. Like
RNase HI, the enzyme’s biological function is unknown.
RNase G (rng/cafA; 55kDa) was initially termed CafA
because it was first determined to be involved in cell division
and the formation of cytoplasmic axial filaments . CafA
shares N-terminal amino acid homology with RNase E,
thus, it was not surprising when the protein was found to
sequences and was subsequently renamed RNase G. Despite
responsible for bulk E. coli mRNA decay . Nonetheless,
RNase G appears to affect the mRNA turnover of at least two
transcripts: fermentative aldehyde dehydrogenase (adhE)
and enolase (eno) [76–78].
RNase BN/Z (elaC; 33kDa) is a nonessential endori-
bonuclease in E. coli. In other organisms, the enzyme
cleaves CCA-less tRNA molecules endonucleolytically [79,
80]. However, all E. coli tRNAs have chromosomally encoded
CCAs and thus are not cleaved by RNase Z. Nonetheless,
RNase Z is able to mature tRNAs in the absence of the
other 4 tRNA maturation exoribonucleases (see below) .
Furthermore, the steady-state levels of over 150 transcripts
increased in the absence of RNase Z including rpsT, cspE,
htpG, glpQ, and adhE .
RNase LS (rnlA; 40kDa) was initially identified as a
regulator of bacteriophage T4 late gene silencing, which is
International Journal of Microbiology5
Table 2: E. coli 3?→ 5?exoribonucleases.
tRNA processing mechanism
Final processing of 3?terminus
Removal of +4, +3, and +2 residues after the 3?CCA
Removal of +4, +3, and +1 residues after the 3?CCA
RNase LS also moderately affects the turnover of several E.
coli transcripts and profoundly affects the stability of bla and
an accumulated fragment of 23S rRNA . It has been
suggested that RNase LS exists in a multiprotein 1000kDa
complex which indicates that the activity of the enzyme is
dependent on interactions with other proteins .
RNase I (rna; 29kDa) is a nonessential and nonspecific
endoribonuclease that resides in the E. coli periplasmic
space which provides a unique mechanism by which the
enzyme’s activity can be tightly regulated. During nonstress
conditions, the cytoplasmic concentration of RNase I is pre-
arrest, RNase I leaks from the periplasmic space into the
cytoplasm where it rapidly degrades rRNA and tRNA .
Variants of RNase I (RNase M and RNase I∗) are present in
E. coli and have been shown to degrade mRNA [86, 87].
Expression of chromosomally encoded toxin-antitoxin
systems enables cells to rapidly shut down cellular processes
in response to changes in growth conditions [88, 89].
and a stable toxin. Under normal growth conditions, the
antitoxin silences the toxin. However, in stress-inducing
antitoxin is rapidly degraded resulting in derepression of
the toxin. Studies on the targets of the toxin components
of these systems have indicated some function as ribonu-
cleases (Table 1; [88, 89]). There are two classes of toxin-
mediated ribonucleases in E. coli: (1) toxins that cleave
mRNA molecules present in ribosomes which include RelE
 and YoeB  and (2) toxins that cleave mRNAs
ChpBK . Both classes of toxin-mediated ribonucleases
inhibit translation and, consequently, protein production by
degrading target transcripts.
2.1.3. Exoribonucleases. Seven E. coli exoribonucleases have
been identified (Table 2). Of these PNPase, RNase II, RNase
R, and Oligo-RNase are established to affect mRNA degrada-
tion and, consequently, protein production. The remaining
exoribonucleases RNase PH [96, 97], RNase D , and
RNase T . are believed to function primarily as tRNA
maturation enzymes; none have been identified to modulate
mRNA turnover. However, it is important to recognize that
formal studies designed to globally measure what effect,
if any, these enzymes have on mRNA turnover have not
been described. Thus, one cannot rule out the possibility
that they may also affect mRNA degradation, and until
proven otherwise, it is possible that virtually any defined
ribonuclease may play a role in the mRNA turnover of
individual or subsets of bacterial transcripts.
RNase R (rnr; 95kDa) is a processive 3?
exoribonuclease that cleaves structured polyadenylated
[poly(A)]mRNA, tRNA, and rRNAs in vitro [100, 101].
Thus, it is thought that the in vivo role of RNase R
is to degrade highly structured RNA molecules, such as
which are associated with stable stem-loops . RNase
R can degrade these secondary structures in the absence
of an RNA helicase provided there is a 3?single-stranded
region, such as a poly(A) tail, available for the enzyme to
bind and initiate decay . RNase R activity increases in
response to several stress conditions including entry into
stationary phase, starvation, and cold shock [102, 103].
During these conditions, RNase R has been proposed to
catalyze degradation of structured RNA molecules when
protein production needs to be stalled .
RNase II (rnb; 72kDa) is a processive 3?→ 5?exori-
bonuclease that accounts for ∼90% of all exoribonucleolytic
activity of poly(A) RNA [51, 104]. The enzyme processes the
3?tail of immature tRNA . It also regulates the stability
of mRNA by removing poly(A) tails which makes them less
accessible to the degradosome [51, 106].
Oligo-RNase (orn; 38kDa) is an essential, processive
cleaves short oligoribonucleotides. The enzyme copurifies
with PNPase suggesting that it may catalyze digestion of
mediated mRNA decay [107, 108].
5?exoribonuclease which, as the name implies,
2.2. RNA Binding Proteins. Another major class of mRNA
turnover regulatory molecules includes RNA binding pro-
teins. As shown in Figure 2, their binding frequently sta-
bilizes or destabilizes mRNA species by affecting the tran-
scripts susceptibility to ribonuclease digestion. Examples of
two well-characterized RNA binding proteins are discussed
The Host factor I protein (Hfq; 11kDa) is an RNA
binding protein that affects mRNA stability by facilitating
base pairing between sRNAs (described below) and their
mRNA targets. This, in turn, can increase or decrease
a transcript’s accessibility to ribonucleases [109–112]. For
example, in rapidly growing cells, outer membrane protein
6 International Journal of Microbiology
RNA binding protein
DestabilizedmRNA Stabilized mRNA
Figure 2: RNA binding proteins affect mRNA stability. RNA bind-
ing proteins affect gene expression by stabilizing or destabilizing
mRNA targets by altering their susceptibility to RNases. RNA
binding proteins may inhibit protein production by destabilizing
mRNA molecules which results in RNase-mediated degradation.
Alternatively, RNases may be inhibited by RNA binding proteins
which stabilizes the mRNA resulting in increased protein produc-
A (ompA) mRNA is stabilized by elements in its 5?UTR
[113, 114]. However, upon entry into stationary phase, the
noncoding sRNA, MicA/SraD, is induced and binds ompA
mRNA [13, 14]. Hfq binds both ompA and the sRNA
in vitro and presumably facilitates base pairing between
these RNAs in vivo [13, 14]. Pairing inhibits ribosome
binding and promotes RNase E-dependent degradation [13,
14]. Additional examples of Hfq-mediated sRNA:mRNA
pairing are discussed below (see Section 2.3). In addition
to catalyzing RNA degradation, Hfq has been shown to
stabilize DsrA, RyhB, and OxyS transcripts, all of which are
well-studied sRNAs. In these cases, Hfq binding overlaps
with RNase E cleavage sites thereby reducing the transcripts’
accessibility to ribonuclease attack . In addition to
its role in facilitating sRNA:mRNA pairing, Hfq stabilizes
transcripts by enhancing the PAP I-mediated elongation of
poly(A) tails in vivo and in vitro .
The carbon storage regulator protein (CsrA; 7kDa)
is a negative regulator of postexponentially induced
metabolic pathways; a positive regulator of glycolysis, acetate
metabolism, and motility; and a repressor of biofilm forma-
tion in E. coli [16–18]. The protein’s regulatory effects are,
in part, due to its ability to modulate the mRNA turnover
of target transcripts. This has been best characterized for
the polycistronic glycogen biosynthesis transcript, glgCAP.
During exponential phase growth when nutrient sources are
readily available, CsrA binds to the 5?UTR of glgCAP mRNA
which, in turn, inhibits ribosome loading and promotes
transcript degradation [18, 117, 118]. During stationary
phase growth, glycogen biosynthesis is upregulated, in part,
because CsrA no longer efficiently binds glgCAP transcripts.
Rather, the protein becomes predominantly sequestered into
a ribonucleoprotein complex comprised of 18 CsrA subunits
and one small RNA, CsrB .
Although not as extensively characterized, CsrA also
seems to regulate the transcript stability and, consequently,
protein production of several virulence factors [16, 17].
However, the effects of CsrA binding appear to be tran-
script specific. For instance, CsrA decreases the half-life of
pgaABCD which prevents PGA (poly-beta-1,6-N-acetyl-d-
glucosamine) production; a cell surface polysaccharide that
promotes biofilm formation . Thus, CsrA’s mechanism
of action may be similar to its role in glgCAP regulation;
binding may inhibit translation initiation and increase
ribonuclease degradation . Conversely, CsrA stabilizes
the flagellar transcriptional activator genes flhDC, presum-
ably by binding to the transcript . Thus, CsrA promotes
motility either by acting as an activator of translation or by
protecting the transcript from ribonuclease digestion .
As described above, Hfq and CsrA are two well-
characterized E. coli RNA binding proteins that influence
protein production by altering mRNA stability. In addition,
the histone-like protein H-NS regulates mRNA stability by
binding to target transcripts . Other H-NS like proteins
regulate mRNA stability as well . Further studies will
likely identify additional RNA binding proteins that regulate
gene expression by altering mRNA stability.
2.3. Small RNAs. The third class of regulatory molecules
80 sRNAs have been identified in E. coli; many of these are
components of stress responsive regulons [122, 123]. sRNAs
typically do not have a discernable open reading frame
encoded in their sequence, thus the RNA molecule rather
than a protein product is thought to affect gene expression.
As described by the Aiba laboratory, the regulatory effects
of sRNAs are mediated largely by their binding to mRNA
and affecting translation which, in turn, mediates turnover
of target transcripts, as shown in Figure 3 . Other
sRNAs such as the ribozyme rnpB, tmRNA, and 4.5S regulate
gene expression through entirely different processes. rnpB
processes tRNA molecules and thus affects translation ,
4.5S is part of the signal recognition particle ribonucleopro-
tein complex that targets membrane and secreted proteins
for translocation during translation , and tmRNA is
a quality control regulator that rescues stalled ribosomes
and facilitates the elimination of proteins whose translation
has been prematurely terminated . In the following
section, we will overview sRNAs that function as antisense
regulatory molecules to influence transcript stability. For
more detailed information regarding the identification and
other mechanisms of sRNA regulation, we refer the reader to
several excellent reviews [122, 123, 127, 128].
One of the best-studied sRNAs is DsrA which affects the
mRNA turnover of at least two target transcripts: hns and
rpoS . As in the case of the RNA binding protein CsrA,
DsrA catalyzes digestion of certain transcripts but stabilizes
International Journal of Microbiology7
Figure 3: Small RNAs base pair with mRNA targets to affect mRNA
stability. Antisense base pairing between sRNAs and their target
transcripts mediates mRNA stability by altering the susceptibility
of the message to RNases and the translation machinery. Pairing
may destabilize mRNA by facilitating RNase-mediated degradation
resulting in translation inhibition. In contrast, pairing may stabilize
mRNA by inhibiting RNase-mediated degradation resulting in
translation of the message and increased protein production.
others. For example, under normal growth conditions,
the stationary phase RNA polymerase sigma factor, rpoS,
transcript is destabilized by the formation of a stable hairpin
in its 5?UTR. Doing so sequesters the ribosome binding
. However, during nonoptimal growth conditions, Hfq
catalyzes antisense base pairing between DsrA and rpoS
enabling efficient translation which stabilizes the message
and results in increased protein production [131, 132]. In
contrast, DsrA base pairing with the histone-like protein
transcript hns inhibits ribosome entry which destabilizes the
message resulting in decreased H-NS abundance .
The ferric uptake regulator, Fur, has classically been
considered a repressor protein but also indirectly activates
gene expression in response to iron availability via an sRNA.
When Fe2+is abundant, Fur becomes activated and inhibits
expression of genes involved in various iron acquisition
systems . Other genes including those involved in
iron storage and intracellular usage are activated by Fur
during these same conditions. Mass´ e and Gottesman have
shown that Fur-mediated gene activation is indirect and
involves the sRNA RyhB . In that study, it was found
that Fur represses RyhB synthesis when iron is abundant
which, in turn, induces the expression of proteins that bind
intracellular iron. However, when iron availability is limited,
Fur becomes inactivated resulting in RyhB upregulation and
repression of target genes. RyhB represses gene expression by
binding to target transcripts in an Hfq-dependent manner
which facilitates RNase E-mediated mRNA degradation
(oxidative stress; ), OmrA/B (osmotic shock; ),
RprA (cell surface stress; ), MicA/SraD (stationary
phase; [13, 14]), MicF (oxidative/antibiotic stress; ),
SgrS (glucose phosphate accumulation; ), and Spot 42
(glucose limitation; ).
We do not intend to give the impression that the
three classes of molecules discussed above, RNases, RNA
binding proteins, and sRNAs, are the sole mediators of
bacterial mRNA turnover. In fact, Deborah Steege published
an excellent review highlighting the identification, charac-
terization, and cellular role of polyadenylation in bacteria
. Poly(A) polymerase I (pcnB; 53kDa) is responsible
for adding 10–40nt poly(A) tails to bacterial RNA species
[142, 143]. Although polyadenylated transcripts account
for only 0.01–2% of the total cellular mRNA content,
polyadenylation plays a significant role in regulating the
stability of target transcripts [142, 143]. Indeed, E. coli
3?→ 5?exoribonucleases RNaseIIandPNPase.Itisbelieved
that poly(A) tails provide a single-stranded extension region
upon which these RNases can bind and initiate decay when
otherwise inhibitory secondary structures are present [142,
144]. For example, increased polyadenylation due to overex-
pression of pcnB in E. coli destabilizes rpoS, trxA, lpp, ompA,
and total RNA . Although polyadenylation promotes
bacterial mRNA decay, the presence of these elements may
also recruit poly(A)-binding proteins, such as CspE, which
when bound to poly(A) tails interfere with RNase activity
. Nonetheless, RNase E can remove poly(A) tails by
poly(A) binding proteins . As mentioned above, RNase
the rpoS poly(A) tail making the transcript less susceptible to
PNPase-mediated decay .
Collectively, ribonucleases, RNA binding proteins, and
noncoding RNA molecules dynamically regulate E. coli gene
expression by affecting mRNA stability. As will become
evident (discussed below), these factors likely modulate
mRNA stability in the model gram-positive organism B.
subtilis and the human pathogen S. aureus as well.
3.Control ofBacillus subtilis Messenger
While studies of the mechanism(s) of E. coli mRNA degra-
dation are still in their infancy, even less is known about the
factors that affect gram-positive bacterial mRNA turnover,
even within the model organism B. subtilis. Here, we will
overview the similarities and differences between B. subtilis
and E. coli mRNA turnover factors.
E. coli and B. subtilis share several ribonuclease sequence
homologues, whereas others are unique to each organism
(Table 1). Particularly striking is the absence of a B. subtilis
sequence homolog to the major component of the E. coli
RNA degradosome RNase E, which, in turn, has delayed
characterization of a B. subtilis RNA degradosome. The lack
of an RNase E homolog is not specific to B. subtilis, rather it
is a common characteristic among gram-positive organisms
with low G-C content. Nonetheless, two ribonucleases,
RNase J1 (rnjA; 61kDa) and J2 (rnjB; 57kDa), have recently
been reported to perform as functional homologues to E. coli
8International Journal of Microbiology
been shown to cleave the B. subtilis thrS mRNA leader with
behavior expected of an RNase E functional homolog .
In addition to affecting transcript specific mRNA decay, the
role of J1/J2 in global mRNA turnover has recently been
described . Interestingly, RNase J1 also functions as a
5?→ 3?exoribonuclease in the maturation of 16S rRNA
and in regulating the mRNA stability of the B. thuringiensis
stationary phase insecticidal protein transcript cryIIIA and
the trp leader sequence [26, 27].
In addition to its role in tRNA processing, the B.
subtilis ribonuclease, RNase P, has been shown to affect
the mRNA stability of the adenine efflux pump transcript,
pbuE . Other ribonucleases that affect the organism’s
mRNA turnover are currently being sought after. Table 1
lists the ensemble of putative B. subtilis ribonucleases that
have been identified to date. It is highly likely that as their
characterization intensifies, a subset of these ribonucleases
will be determined to affect mRNA stability.
As with the B. subtilis RNA degradation machinery,
the organism’s RNA binding proteins have not been fully
characterized. Studies have revealed that certain RNA bind-
ing protein functions are conserved across species, whereas
others are not. For instance, as in the case of E. coli, B. subtilis
CsrA may affect mRNA degradation . The protein
binds to the hag (flagellin) transcript, inhibits translation
initiation, and prevents cell motility. However, it remains to
be seen whether CsrA binding effects hag mRNA stability
. Conversely, despite its importance in mediating
for B. subtilis sRNA:mRNA duplex formation .
Likewise, the biological role(s) and mechanism of action
of B. subtilis sRNAs have not been as extensively char-
acterized as their E. coli counterparts. Nonetheless, recent
work suggests that B. subtilis sRNAs are produced and do
have regulatory functions. Silvaggi et al. found a set of
sRNAs that are induced in response to sporulation .
Further, Heidrich et al. have shown that the B. subtilis
catabolism [150, 152]. As these and other investigators
unravel the details of B. subtilis sRNA production, effects,
and mechanism of action, it will be exciting to determine the
As described above, several studies are in progress to
characterize mechanisms that alter mRNA turnover in B.
subtilis. However, additional studies in this organism are
certainly required to further characterize the components
described here and identify additional factors that influence
this mechanism of gene regulation. Although B. subtilis is
considered the model gram-positive organism for studying
cellular processes, it is in fact quite different from other
gram-positive bacteria. For example, the organism is motile
and undergoes sporulation, whereas other gram-positive
bacteria, such as S. aureus, do not. Likewise, RNA turnover
mechanisms may not be conserved across all gram-positive
have recently been described and may play a dynamic role in
virulence and adaptation to stress responses in the human
pathogen S. aureus.
4.Control ofStaphylococcus aureus
Messenger RNA Degradation
As discussed above, studies from E. coli and B. subtilis have
provided insight into the processes that regulate bacterial
RNA stability. Until recently, this mechanism of gene regula-
tion was largely uncharacterized within the human pathogen
S. aureus. In this final section, we discuss emerging efforts to
characterize factors that contribute to RNA turnover in this
Recent studies have revealed that S. aureus mRNA
turnover is a highly dynamic process. Indeed, during log
phase growth the half-life of ∼85% of S. aureus transcripts
is ≤2.5 minutes, yet many transcripts are stabilized as cells
transition to stationary phase growth; the half-life of only
∼48% of mRNA species is ≤2.5 minutes (Anderson and
Dunman, unpublished; [11, 22]). While the biological sig-
unknown, a similar phenotype has been observed following
induction of heat shock, cold shock, the stringent response,
acid shock, and alkaline shock responses (Anderson and
Dunman, unpublished; ). Collectively, these results
indicate that altering mRNA stability may provide a dynamic
means by which S. aureus cells can rapidly adapt to adverse
growth conditions without the need to induce de novo
Although the ribonucleases that contribute to S. aureus
global mRNA turnover have not yet been characterized, a
transcript specific ribonuclease, RNase III, has been shown
to affect the mRNA decay of virulence factors [23, 24].
During the postexponential growth phase, the noncoding-
like RNA molecule, RNAIII, base pairs with spa (protein
A). This, in turn, facilitates RNase III-mediated spa mRNA
decay [23, 24]. One additional RNase, RNase P, has been
previously studied in S. aureus [64, 153]. As described for
E. coli, this ribonuclease is presumably responsible for tRNA
maturation but may contribute to mRNA decay as well.
BLAST analyses suggest that S. aureus harbors at least 14
B. subtilis RNase homologues (Table 1; [92, 154]). At least
one of these, PNPase (pnpA; 77kDa), affects global mRNA
turnover. As in the case for E. coli, disruption of the S.
aureus pnpA gene results in a mild global change in mRNA
stability (Figure 4) suggesting that other ribonucleases can
S. aureus pnpA-mutant cells demonstrate appreciable cold
sensitivity when transferred to 10◦C suggesting that mRNA
turnover may play a significant role in the organism’s ability
of S. aureus mRNA turnover, coupled to the importance
of PNPase in cold shock adaptation, it is likely that the
modulation of mRNA turnover is an important regulatory
system for this organism to adapt to otherwise deleterious
Nonetheless, an Hfqhomolog hasbeen identified butin con-
trast to E. coli, S. aureus Hfq is not required for sRNA:mRNA
duplex formation, stress adaptation, virulence, or metabolic
acid binding protein staphylococcal accessory regulator,
International Journal of Microbiology9
0.0010.010.11 10 100100010000
0.0010.010.11 10 100 1000 10000
Figure 4: Degradation profiles of S. aureus wild type and pnpA-mutant cells. RNA signal intensity values for each GeneChip transcript are
plotted at 0 minute (T0; X-axis) and 5 minutes (T5; Y-axis) posttranscriptional arrest. Red represents transcripts considered “present” in
both T0 and T5 samples (Affymetrix algorithms). Yellow represents transcripts that are “absent” in both samples. Blue represents transcripts
that are present in one sample but absent in the second. Grey dashed lines indicate calculated lower limit of sensitivity for each sample.
Results show that following 5 minutes of transcriptional arrest, 51.1% (1287 transcripts) of mRNA species are completely degraded within
wild type S. aureus cells. Conversely, 17.6% (444 transcripts) of mRNA species were undetectable within isogenic pnpA-mutant cells at 5
minutes posttranscriptional arrest, suggesting that PNPase plays a role in global S. aureus mRNA turnover.
SarA, may affect mRNA turnover. That study showed that a
product of the sarA locus influences the stability of several
transcripts including two surface expressed virulence factor
transcripts, spa and cna (collagen adhesion protein) .
SarA may directly or indirectly affect mRNA stability by
binding target transcripts or regulating another factor which
binds mRNA, respectively.
As mentioned above, S. aureus produces a well-
characterized noncoding-like RNA regulator, RNAIII, which
modulates virulence factor transcript stability [23, 24].
The regulatory effects of RNAIII are modulated by the
RNA molecule rather than the protein product of this
locus . Thus, there is precedence for the existence of
additional S. aureus sRNA-like regulators. Indeed, Pichon
and Felden identified twelve sRNA-like molecules that are
specific manner. Seven of these are encoded on S. aureus
pathogenicity islands and are presumably involved in the
regulation of virulence factors. Of these, one was shown, in
vitro, to base pair with the 3?UTR of an ABC transporter
mRNA . Although not formally evaluated, it is likely
that duplex formation affects mRNA stability. Moreover,
we recently found that S. aureus produces 139 small stable
(half-lives ≥30 minutes following transcriptional arrest)
RNA molecules [11, 22]. Based on their size, absence of an
transcriptional unit, it is likely that they constitute additional
sRNA-like molecules. Nearly all of these small stable RNAs
are differentially expressed in response to growth phase and
stress conditions. Thus, we predict that S. aureus small RNAs
metabolism, and adaptation to otherwise deleterious growth
Global and transcript specific studies indicate that the
regulation of gene expression by altering mRNA stability is a
dynamic and previously unappreciated means of controlling
gene expression in S. aureus. Certainly, further studies are
needed to determine the function of each ribonuclease,
identify the regulatory cues that mediate alterations to
mRNA stability, and establish the biological significance of
altering mRNA stability in this important human pathogen.
5. Concluding Remarks
The modulation of mRNA turnover is a recently appreciated
regulatory phenomenon that spans most, if not all, bac-
terial species. Presumably, altering the mRNA degradation
properties of individual or subsets of mRNA species allows
the cell to quickly adapt to endogenous or exogenous
cues without having to expend the energy required for
de novo transcript synthesis. A survey of the three factors
described here, ribonucleases, RNA binding proteins, and
sRNAs among three genetically divergent organisms, sug-
gests that mechanisms of modulating mRNA turnover are
generally conserved across bacteria. As the field matures,
it is likely that additional conserved RNA stabilization and
destabilization processes will be identified. Despite these
similarities, it is also obvious that species specific differences
do occur. Perhaps this is most evident by the absence
of a sequence homolog to the central component of the
E. coli RNA degradosome, RNase E, among gram-positive
10International Journal of Microbiology
bacteria. Clearly, further studies are required to better
characterize already identified members of each organism’s
mRNA turnover machinery and to expand identification of
previously unrecognized components.
The authors would like to thank Lisa J. Kuechenmeister
for technical assistance in figure preparation and Patrick
D. Olson for his dedication to characterizing S. aureus
ribonucleases. The second author is supported by University
of Nebraska Medical Center development funds, American
Heart Association award 0535037N, and NIH/NIAID award
Heart Association predoctoral fellowship 0715547Z.
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