Mechanisms of cross-talk between the ubiquitin-proteasome and
Viktor I. Korolchuk, Fiona M. Menzies, David C. Rubinsztein*
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, UK
a r t i c l e i n f o
Received 1 December 2009
Revised 22 December 2009
Accepted 23 December 2009
Available online 28 December 2009
Edited by Noboru Mizushima
a b s t r a c t
The ubiquitin proteasome system (UPS) and macroautophagy (hereafter called autophagy) were, for
a long time, regarded as independent degradative pathways with few or no points of interaction.
This view started to change recently, in the light of findings that have suggested that ubiquitylation
can target substrates for degradation via both pathways. Moreover, perturbations in the flux
through either pathway have been reported to affect the activity of the other system, and a number
of mechanisms have been proposed to rationalise the link between the UPS and autophagy. Here we
critically review these findings and outline some outstanding issues that still await clarification.
? ? 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
The UPS and autophagy are two cornerstones of cellular catab-
olism that are involved in most aspects of normal physiology and
development, and are also implicated in a broad array of patholog-
ical states, including cancer, neurodegeneration and aging. Protein
degradation controls processes like the cell cycle, signaling, DNA
transcription, repair and translation, by downregulating their crit-
ical regulatory elements. Additionally, the UPS and/or autophagy
are involved in the degradation of virtually every type of surplus,
dysfunctional or damaged cellular component, ranging from solu-
ble proteins to whole organelles. This allows recycling of both mat-
ter and energy and therefore serves to save valuable resources.
Thus, autophagy and the UPS are critical in the maintenance of cel-
lular homeostasis, suggesting that their activities need to be care-
fully orchestrated. Yet, the two pathways differ so significantly
with respect to their mechanistic details (autophagy is a vesicular
trafficking pathway, while the enzymatic reactions of the UPS oc-
cur directly in the cytosol), substrates (the activity of UPS is re-
stricted to soluble proteins, while autophagy is practically
omnivorous), machinery, specificity, kinetics, elements of control,
etc., that this leaves very little room to suspect any cross-talk. In-
deed, for a long time these processes were viewed as independent
of each other [1,2]. Here, we review the evidence generated during
recent years that challenge this view and offer a glance into a com-
plex and often an unexpected interplay between these two cellular
2. Basic mechanics of the UPS and autophagy
Proteins are targeted for destruction by the UPS via a series of
enzymatic reactions that tag them with homopolymers of a
small, 76-amino acid residue, protein called ubiquitin [3,4]. Poly-
ubiquitylation marks the UPS clients for transportation by a
poorly understood shuttling machinery to a specialized organelle
called the proteasome, where proteins are degraded to oligopep-
tides, which are released into the cytoplasm or nucleoplasm,
where they can be digested into amino acids by soluble pepti-
dases. The specificity and selectivity of the ubiquitylation process
is achieved by a combination of three types of enzymes . E1
enzymes, two of which are known in mammals, initiate the reac-
tion by activating ubiquitin and transferring it onto E2 ubiquitin-
conjugating molecules, of which around 40 are thought to be
encoded in the mammalian genome. A substrate is selected in
our cells by one of several hundred E3 ligases, which bind the
0014-5793/$36.00 ? 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Fax: +44 1223 331206.
E-mail address: email@example.com (D.C. Rubinsztein).
FEBS Letters 584 (2010) 1393–1398
journal homepage: www.FEBSLetters.org
ubiquitin-carrying E2 enzyme, resulting in the transfer of the
ubiquitin onto lysine residues of the target substrate [6,7]. As a
result of such a reaction, the substrate becomes monoubiquity-
lated in one or more places. These initial modifications are not
yet sufficient for proteasomal targeting. Since ubiquitin itself
contains lysine residues in positions 6, 11, 27, 31, 33, 48 and
63, all of these sites could become acceptors of another ubiquitin
moiety in a subsequent round of ubiquitylation, which would
lead to the generation of different types of polyubiquitin chains.
It is thought that chains of at least four ubiquitins  intercon-
nected via K48 residues, which are characterized by a closed
conformation , are optimal for delivery to the proteasome.
The proteasome is a barrel-shaped proteolytic organelle found
throughout the cell that consists of a 20S central complex and
two 19S lid complexes. The 19S complexes bind cargo-loaded
shuttling proteins, deubiquitylate the substrates and control
access to the six proteolytic sites of the inner core of 20S sub-
unit [10,11]. The catalytic activities of the proteasome have dif-
ferent specificities, and are considered trypsin-, chymotrypsin-
and peptidyl-glutamyl peptide-hydrolyzing-like . The narrow
size of the proteasomal catalytic pore suggests that protein sub-
strates need to be partially-unfolded prior to entry into the 20S
subunit. Thus, protein complexes and aggregates can only be
digested if disassembled, which makes them poor proteasome
In contrast to the UPS, autophagy is restricted to the cytoplasm,
but is capable of degrading a much wider spectrum of substrates,
which, on average, tend to be longer-lived and bulkier. These in-
clude functional or misfolded soluble proteins, protein complexes,
oligomers and aggregates. Although limited, there appears to be a
certain overlap in function between the two degradative pathways,
as both seem to be capable of degrading soluble misfolded poly-
peptide chains . Additionally, autophagy can degrade whole
cellular organelles. Terms like pexophagy, mitophagy or ribophagy
have been coined to describe autophagosomal degradation of per-
oxisomes, mitochondria or ribosomes, respectively. Interestingly,
also, proteasomal subunits were found to be degraded by lyso-
somes . This provides a possibility that the autophagy-lyso-
some system could affect the activity of the UPS by controlling
the numbers of proteasomes, a hypothesis that, to our knowledge,
has not yet been investigated.
Autophagy is initiated by the formation and elongation of a
double-layered isolation membrane (the origin of which remains
an intensely debated topic) also called a phagophore, that enwraps
and sequesters portions of cytoplasm containing autophagic sub-
strates, to form autophagosomes. The formation of autophago-
somes is regulated by a set of Atg genes, where Atg stands for
autophagy-related, the nomenclature taken from yeast where they
were originally identified . These can be grouped, according to
their function, into the Atg1 complex (Atg1, Atg13 and Atg17 con-
trolling autophagosomal induction), the PI3K complex III (includ-
ing phosphatidyl inositol 3-phosphate kinase vps34, Beclin 1
(Atg6 orthologue) and UVRAG (UV radiation resistance associated
gene)) regulating vesicle nucleation, and two interconnected ubiq-
uitin-like conjugation systems that mediate vesicle elongation and
sealing. The first of these conjugation systems involves the forma-
tion of Atg5-12 conjugate, mediated by the E1-like enzyme, Atg7,
and the E2-like enzyme, Atg10. The second involves conjugation
of Atg8 (in mammalian cells also known as microtubule-associated
protein 1 light chain 3, LC3) to the lipid, phosphatidylethanol-
amine, regulated by Atg7, along with Atg3, as the E2-like enzyme
. Following the formation of autophagosome, Atg5-12 conju-
gate is removed from the vesicle, while LC3 remains attached.
Thus, LC3 serves as a reliable autophagosomal marker that can
be used to estimate both the rates of autophagosome formation
and degradation . Autophagosomes are transported along
microtubules in a dynein-dependent manner and fuse with endo-
somes or directly with lysosomes where autophagosomal contents
are degraded by lysosomal hydrolases .
3. Ubiquitin as a unifying factor linking the UPS and selective
Autophagy is often thought of as a non-specific process that de-
grades cytoplasmic proteins and organelles in bulk, a situation
likely to occur when cell survival depends on autophagy during
periods of starvation . However, as early as the 1970s, the first
evidence of selective autophagy was suggested for organelles such
as the endoplasmic reticulum or mitochondria, although further
understanding of such selectivity was impossible until more recent
insights into the molecular mechanisms of selective autophagy
. While this process is still poorly understood, it is postulated
that during selective autophagy, certain autophagic substrates
may be specifically targeted for destruction, rather than being ran-
domly taken up along with bulk cytoplasm. The relevance of this
issue to the topic of our discussion becomes evident when we learn
that it is ubiquitylation, just like in the ubiquitin proteasome path-
way, that serves as the signal for selective autophagy. Thus, it
might be tempting to speculate that ubiquitin coordinates the
catabolism of cellular targets by both the UPS and autophagy. In-
deed, many proteins are known to be substrates of both degrada-
tive systems, and in certain conditions ubiquitylated proteasomal
substrates, which are normally degraded by the UPS, can also be di-
gested by autophagy, and vice versa [22–24]. Moreover, impair-
ment of proteasome activity was found to activate autophagy,
which was thought to be a compensatory mechanism allowing
the cell to reduce the levels of UPS substrates (see below) [25–
28]. However, the overall contribution of autophagy to the degra-
dation of the total pool of cellular ubiquitylated proteins remains
unknown, and so it is unclear whether ubiquitylation is an impor-
tant mechanism for autophagic targeting of many proteins.
In addition, although ubiquitylation may appear to be a univer-
sal tag targeting substrates for destruction via both catabolic sys-
tems, the exact type of modification recognised by each pathway
appears to be different. While K48-linked polyubiquitin chains
are employed by the UPS, substrates recognised by autophago-
some-lysosome pathway are thought to be modified either by
K63-linked chains (adopting a more open conformation than K48
chains), or may just be monoubiquitylated . Thus, despite the
use of ubiquitin in both catabolic pathways, the structural com-
plexity of different polyubiquitin chains may be sufficient to main-
tain selectivity and specificity of the UPS and autophagy towards
their substrates. However, some potential overlap may result from
incomplete specificity of the different adaptor molecules that have
been proposed to retrieve ubiquitylated substrates for each degra-
dative pathway. In this category, there are several proteins that ap-
pear to serve as linkers between ubiquitylated cargo and the
phagophore, including p62 (also called SQSTM1/A170), NBR1
(neighbour of BRCA1 gene 1), HDAC6 (histone deacetylase 6) and
Alfy . These proteins have the capacity to interact directly or
indirectly with both ubiquitin and components of autophagic
machinery, thus providing the type of link that would be required
from an adaptor molecule. The most established of these adaptors,
p62, is itself an autophagy substrate that forms homo-oligomers to
which ubiquitylated proteins are recruited via its UBA (ubiquitin-
associated) domain [30–33]. It was proposed that these complexes
serve to sequester ubiquitylated substrates that are recognised by
the autophagic machinery (p62 interacts directly with LC3 via a
dedicated LIR motif ), and then engulfed and degraded
[30,31]. The UBA domain of p62 appears to have a slightly higher
affinity for monoubiquitin or polyubiquitin chains with open
conformations (K63-linked), compared to those with a closed
V.I. Korolchuk et al./FEBS Letters 584 (2010) 1393–1398
conformations (K48-linked) . This, on the one hand, may sug-
gest a preference of autophagy for substrates tagged with single
ubiquitin, short chains, or with longer K63 chains. On the other
hand, this might allow K48 chain-tagged substrates to still be re-
cruited into autophagosomes, especially in circumstances when
the UPS is compromised, and when the concentration of K48-poly-
ubiquitylated proteins is sufficient to allow such chains to interact
effectively with p62 [23,34]. Indeed, a mild accumulation of pri-
marily K63-linked polyubiquitin-tagged proteins was observed in
p62-deficient mouse tissues. The interpretation of this effect is
complex, since p62 also appears to serve as an adaptor for prote-
asomal degradation of certain ubiquitylated proteins and is further
complicated by suggestions of ubiquitin-independent roles for p62
in the degradation of some autophagy substrates [22,35]. Never-
theless, these studies are consistent with the idea that p62 can
serve as an adaptor required for autophagic degradation of ubiqui-
tylated proteins [30,36].
The idea of the unifying role of ubiquitin in the UPS and selec-
tive autophagy has recently been discussed in detail elsewhere
[14,30,37], and so we will next focus on the more specific question
of how changes in the activity of one of the degradative pathways
affect the flux through the other system.
4. Impairment of the UPS is compensated by upregulation of
One of the proposed links between the UPS and autophagy is
based on the observation that impairment of the UPS leads to in-
creased autophagic function [25–27]. This is commonly considered
to be a compensatory mechanism, allowing cells to reduce the bur-
den of accumulated UPS substrates. Indeed, treatment of both cells
and mice with rapamycin to upregulate autophagy has been dem-
onstrated to protect against cell death caused by proteasome inhi-
bition  and upregulation of autophagy has been shown to
protect against genetic loss of proteasome activity in Drosophila
. Unfortunately, there is little consensus on the exact mecha-
nism(s) of this cross-talk, as several potential explanations have
been suggested. One such proposed mechanism involves activation
of endoplasmic reticulum (ER) stress, due to the accumulation of
misfolded proteins that leads to the induction of the unfolded pro-
tein response (UPR). The UPR is an ER-to-nucleus signaling path-
way that results in the transcriptional activation of variety of
genes, including those involved in protein folding and degradation
in the ER. The activation of this pathway has been shown by a
number of studies to result in the activation of autophagy (re-
viewed in ). There are discrepancies in the exact mechanics
of this phenomenon, and it is likely to depend on the cell type
and stimulus for the UPR. Investigations into the direct link be-
tween proteasome inhibition, UPR and autophagy have been car-
riedoutin two studiesusing
bortezomid. These studies both demonstrate the importance of
the transcription factor ATF4 in the upregulation of autophagy
genes following proteasome inhibition. However, the study of
Zhu et al. suggests that the mechanism for increased ATF4 level
is the activation of the PERK arm of the UPR requiring the phos-
phorylation of eIF2a , whereas Milani et al. suggest that direct
stabilisation of the ATF4 protein due to the loss of proteasome
activity, independent of the upstream activity of PERK, results in
its increased activity . Additionally these studies diverge on
the downstream targets of ATF4 action, showing an increase in
either ATG5 and ATG7 transcription , or LC3 expression .
Additionally, another study has suggested that compensatory
autophagy upregulation following treatment with MG132, or bort-
ezomib, is mediated by the IRE1 arm of the UPR and its down-
stream target c-Jun NH2-terminal kinase (Jnk1) [26,41]. More
recent studies have demonstrated that Jnk1, in turn, may induce
autophagy by phosphorylation of Bcl-2, thereby disrupting its
autophagy–inhibitory interaction with Beclin 1 [26,41].
Independently of the UPR, proteasome inhibition in dopaminer-
gic neurons has been shown to induce autophagy via a mechanism
requiring p53 . Following proteasome inhibition, levels of p53
are increased, , and multiple pathways have been elucidated
through which increases in p53 are suggested to upregulate
autophagy, including activation of APMK and subsequent inhibi-
tion of mTOR and induction of damage-regulated autophagy mod-
ifier (DRAM) (reviewed in ).
The protective effect of the compensatory upregulation of
autophagy in proteasome-inhibited cells has also been suggested
to be dependent on HDAC6 [25,27]. However, the role for HDAC6
in this process is not thought to be through signaling to increase
autophagic flux, but rather through ensuring efficient delivery of
substrates to the autophagic machinery for degradation. HDAC6
was earlier found to regulate the formation of perinuclear ubiqui-
tylated inclusion bodies, called aggresomes . The concentration
of misfolded proteins into these aggresomes has been hypothe-
sised to allow them to be degraded more efficiently by autophagy
. Additionally, HDAC6 is thought to mediate the transport of
components of the autophagic machinery to the aggresome .
Overall, while there is a general consensus about a compensa-
tory role of autophagy following proteasomal inhibition, the exact
mechanisms of this link requires further clarification (Fig. 1). These
different mechanisms may not be mutually-exclusive and may also
be of different importance in different cell types or at different
time-points after the proteasome is inhibited.
5. Effect of autophagy on the UPS
Genetic studies in mice demonstrated that inactivation of
autophagy by the knockout of essential autophagic genes (Atg5
or Atg7) results in the accumulation and aggregation of ubiquity-
lated proteins [45,46]. There are several possible interpretations
of this result. One of them is in line with the idea that ubiquitylated
proteins could be degraded by autophagy, although it is currently
unknown whether the type of polyubiquitin chains accumulating
in autophagy-deficient tissues is consistent with the proposed
specificity of autophagy for K63-linked polyubiquitin chains, the
extent to which autophagy contributes to the degradation of the
total pool of cellular ubiquitylated proteins, or whether the accu-
mulation of ubiquitylated autophagic substrates can alone explain
the profound accumulation of ubiquitin seen in autophagy-defi-
cient mice. Another possibility is that autophagosomal clients that
initially are not ubiquitylated, remain for long enough in autoph-
agy-deficient cells to eventually become modified with ubiquitin.
Finally, autophagy impairment could impact on the flux through
the UPS. Indeed, we and others support this last hypothesis, as
we found that impaired autophagy also leads to the impaired deg-
radation of specific UPS clients [47–49]. Our data suggested that
the decreased UPS flux in autophagy-compromised cells was not
due to impaired catalytic activity of proteasomes isolated from
them. Instead, we found that the block in the UPS function is med-
iated by accumulation of p62, as its knockdown rescued the levels
of UPS substrates in autophagy-deficient cells. In addition, overex-
pression of p62 alone was sufficient to inhibit the UPS, an effect
partially dependent on its UBA domain. Since p62 competes with
other ubiquitin-binding proteins involved in proteasomal degrada-
tion, like p97/VCP (valosin-containing protein), for binding to ubiq-
uitylated proteins, we proposed that elevated levels of p62 may
deny such shuttling proteins access to ubiquitylated UPS sub-
strates (Fig. 2) [47,48]. These findings help to explain how knock-
out of p62 rescues the increased levels of soluble and aggregated
V.I. Korolchuk et al./FEBS Letters 584 (2010) 1393–1398
ubiquitylated proteins observed in autophagy-deficient tissues
. Thus, p62 has been implicated in two different, but not mutu-
ally-exclusive, mechanisms of cross-talk between the UPS and
autophagy. In the physiological state, where autophagy operates
at normal rates, p62 could serve to deliver ubiquitylated proteins
for autophagosomal destruction [30,31,33]. In contrast, in situa-
links between pathways
Fig. 1. A diagram illustrating possible mechanisms of compensatory autophagic upregulation following UPS inhibition. Unfolded protein response, elevated levels of p53 and
the increased aggregation of ubiquitylated proteins mediated by HDAC6, have all been implicated in the cross-talk between the UPS and autophagy.
1. Soluble UPS substrates e.g. p53
accumulate – toxicity/apoptosis
2. p62 aggregates itself which may
account for most/all ubiquitin
links between pathways
Fig. 2. Inhibition of autophagy impairs the UPS function. p62, which accumulates due to autophagy blockade, binds ubiquitylated proteins and prevents their delivery to and
degradation by the proteasome. Toxicity due to elevated levels of certain UPS substrates, like p53, and accumulation of ubiquitinated p62-positive aggregates are the
components of the autophagic deficiency phenotype.
V.I. Korolchuk et al./FEBS Letters 584 (2010) 1393–1398
tions where autophagy becomes impaired (which occurs in a vari-
ety of pathological conditions, including certain neurodegenerative
conditions, such as lysosomal storage disorders), p62 becomes a
Trojan horse due to its binding (probably non-selectively because
of elevated levels) to ubiquitylated proteins and preventing their
delivery to the proteasome for degradation. The lack of compensa-
tion for autophagy dysfunction by the UPS is in agreement with the
fact that p62, when accumulates, oligomerizes and therefore
would be too bulky to be a good substrate for the proteasome with
its narrow catalytic pore.
A special case of coordination between the two degradative sys-
tems comes from Goldberg and colleagues, who demonstrated that
both the UPS and autophagy contribute to muscle atrophy in phys-
iological conditions, like fasting, as well as in diseases character-
ised by muscle wasting . In this case, coordinate upregulation
of both catabolic pathways was induced by the FoxO3 transcription
factor downstream of the IGF-1/PI3K/Akt signaling axis. It would
be interesting to investigate if coordinated induction of both deg-
radative pathways could be achieved in other tissues, like the
6. Concluding remarks
Extensive effort has been invested during the last decade into
studies of the fine molecular detail of both the UPS and autophagy.
This has allowed us to begin the ascent to another level, where we
aim to learn how different degradative pathways are integrated as
components of cellular catabolism. This may be important when
we want to manipulate one of the pathways for therapeutic goals.
Furthermore, it will be interesting to test if the development of the
pathology caused by primary deficiency in one degradative system
could be largely affected by secondary changes in the other
We are grateful to the Wellcome Trust (Senior Fellowship to
D.C.R.), MRC, and NIHR Biomedical Research Centre at Adden-
brooke’s Hospital for funding our work in this area.
 Ciechanover, A., Finley, D. and Varshavsky, A. (1984) Ubiquitin dependence of
selective protein degradation demonstrated in the mammalian cell cycle
mutant ts85. Cell 37, 57–66.
 Pickart, C.M. (2004) Back to the future with ubiquitin. Cell 116, 181–190.
 Ciechanover, A., Heller, H., Elias, S., Haas, A.L. and Hershko, A. (1980) ATP-
dependent conjugation of reticulocyte proteins with the polypeptide required
for protein degradation. Proc. Natl. Acad. Sci. USA 77, 1365–1368.
 Hershko, A., Ciechanover, A., Heller, H., Haas, A.L. and Rose, I.A. (1980)
Proposed role of ATP in protein breakdown: conjugation of protein with
multiple chains of the polypeptide of ATP-dependent proteolysis. Proc. Natl.
Acad. Sci. USA 77, 1783–1786.
 Hershko, A., Heller, H., Elias, S. and Ciechanover, A. (1983) Components of
ubiquitin-protein ligase system. Resolution, affinity purification, and role in
protein breakdown. J. Biol. Chem. 258, 8206–8214.
 Pickart, C.M. and Eddins, M.J. (2004) Ubiquitin: structures, functions,
mechanisms. Biochim. Biophys. Acta 1695, 55–72.
 Randow, F. and Lehner, P.J. (2009) Viral avoidance and exploitation of the
ubiquitin system. Nat. Cell Biol. 11, 527–534.
 Thrower, J.S., Hoffman, L., Rechsteiner, M. and Pickart, C.M. (2000) Recognition
of the polyubiquitin proteolytic signal. EMBO J. 19, 94–102.
 Fushman, D. and Walker, O. (2009) Exploring the linkage dependence of
polyubiquitin conformations using molecular modeling. J. Mol. Biol. 12, 23.
 Kopp, F., Steiner, R., Dahlmann, B., Kuehn, L. and Reinauer, H. (1986) Size and
shape of the multicatalytic proteinase from rat skeletal muscle. Biochim.
Biophys. Acta 872, 253–260.
 Lowe, J., Stock, D., Jap, B., Zwickl, P., Baumeister, W. and Huber, R. (1995)
Crystal structure of the 20S proteasome from the archaeon T. acidophilum at
3.4 A resolution. Science 268, 533–539.
 Heinemeyer, W., Fischer, M., Krimmer, T., Stachon, U. and Wolf, D.H. (1997)
The active sites of the eukaryotic 20 S proteasome and their involvement in
subunit precursor processing. J. Biol. Chem. 272, 25200–25209.
 Nandi, D., Tahiliani, P., Kumar, A. and Chandu, D. (2006) The ubiquitin-
proteasome system. J. Biosci. 31, 137–155.
 Ding, W.X. and Yin, X.M. (2008) Sorting, recognition and activation of the
misfolded protein degradation pathways through macroautophagy and the
proteasome. Autophagy 4, 141–150.
 Cuervo, A.M., Palmer, A., Rivett, A.J. and Knecht, E. (1995) Degradation of
proteasomes by lysosomes in rat liver. Eur. J. Biochem. 227, 792–800.
 Klionsky, D.J. et al. (2003) A unified nomenclature for yeast autophagy-related
genes. Dev. Cell 5, 539–545.
 Suzuki, K. and Ohsumi, Y. (2007) Molecular machinery of autophagosome
formation in yeast, Saccharomyces cerevisiae. FEBS Lett. 581, 2156–2161.
 Klionsky, D.J. et al. (2008) Guidelines for the use and interpretation of assays
for monitoring autophagy in higher eukaryotes. Autophagy 4, 151–175.
 Ravikumar, B., Acevedo-Arozena, A., Imarisio, S., Berger, Z., Vacher, C., O’Kane,
C.J., Brown, S.D. and Rubinsztein, D.C. (2005) Dynein mutations impair
autophagic clearance of aggregate-prone proteins. Nat. Genet. 37, 771–776.
 Ciechanover, A. (2005) Proteolysis: from the lysosome to ubiquitin and the
proteasome. Nat. Rev. Mol. Cell Biol. 6, 79–87.
 Klionsky, D.J.(2007) Autophagy:
understanding in less than a decade. Nat. Rev. Mol. Cell Biol. 8, 931–937.
 Wooten, M.W., Geetha, T., Babu, J.R., Seibenhener, M.L., Peng, J., Cox, N., Diaz-
Meco, M.T. and Moscat, J. (2008) Essential role of sequestosome 1/p62 in
regulating accumulation of Lys63-ubiquitinated proteins. J. Biol. Chem. 283,
 Fuertes, G., Villarroya, A. and Knecht, E. (2003) Role of proteasomes in the
degradation of short-lived proteins in human fibroblasts under various growth
conditions. Int. J. Biochem. Cell Biol. 35, 651–664.
 Fuertes, G., Martin De Llano, J.J., Villarroya, A., Rivett, A.J. and Knecht, E. (2003)
Changes in the proteolytic activities of proteasomes and lysosomes in human
fibroblasts produced by serum withdrawal, amino-acid deprivation and
confluent conditions. Biochem. J. 375, 75–86.
 Pandey, U.B. et al. (2007) HDAC6 rescues neurodegeneration and provides an
essential link between autophagy and the UPS. Nature 447, 859–863.
 Ding, W.X., Ni, H.M., Gao, W., Yoshimori, T., Stolz, D.B., Ron, D. and Yin, X.M.
(2007) Linking of autophagy to ubiquitin-proteasome system is important for
the regulation of endoplasmic reticulum stress and cell viability. Am. J. Pathol.
 Iwata, A., Riley, B.E., Johnston, J.A. and Kopito, R.R. (2005) HDAC6 and
microtubulesare requiredfor autophagic
huntingtin. J. Biol. Chem. 280, 40282–40292.
 Milani, M., Rzymski, T., Mellor, H.R., Pike, L., Bottini, A., Generali, D. and Harris,
A.L. (2009) The role of ATF4 stabilization and autophagy in resistance of breast
cancer cells treated with Bortezomib. Cancer Res. 69, 4415–4423.
 Welchman, R.L., Gordon, C. and Mayer, R.J. (2005) Ubiquitin and ubiquitin-
like proteins as multifunctional signals. Nat. Rev. Mol. Cell Biol. 6, 599–
 Kirkin, V., McEwan, D.G., Novak, I. and Dikic, I. (2009) A role for ubiquitin in
selective autophagy. Mol. Cell 34, 259–269.
 Bjorkoy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A.,
Stenmark, H. and Johansen, T. (2005) P62/SQSTM1 forms protein aggregates
degraded by autophagy and has a protective effect on huntingtin-induced cell
death. J. Cell Biol. 171, 603–614.
 Komatsu, M. et al. (2007) Homeostatic levels of p62 control cytoplasmic
inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163.
 Pankiv, S. et al. (2007) P62/SQSTM1 binds directly to Atg8/LC3 to facilitate
degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem.
 Long, J., Gallagher, T.R., Cavey, J.R., Sheppard, P.W., Ralston, S.H., Layfield, R.
and Searle, M.S. (2008) Ubiquitin recognition by the ubiquitin-associated
domain of p62 involves a novel conformational switch. J. Biol. Chem. 283,
 Geetha, T., Seibenhener, M.L., Chen, L., Madura, K. and Wooten, M.W. (2008)
P62 serves as a shuttling factor for TrkA interaction with the proteasome.
Biochem. Biophys. Res. Commun. 374, 33–37.
 Kirkin, V., Lamark, T., Johansen, T. and Dikic, I. (2009) NBR1 cooperates with
p62 in selective autophagy of ubiquitinated targets. Autophagy 5, 732–733.
 Lamark, T., Kirkin, V., Dikic, I. and Johansen, T. (2009) NBR1 and p62 as cargo
receptors for selective autophagy of ubiquitinated targets. Cell Cycle 8, 1986–
 Pan, T., Kondo, S., Zhu, W., Xie, W., Jankovic, J. and Le, W. (2008)
Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via
autophagy enhancement. Neurobiol. Dis. 32, 16–25.
 Hoyer-Hansen, M. and Jaattela, M. (2007) Connecting endoplasmic reticulum
stress to autophagy by unfolded protein response and calcium. Cell Death
Differ. 14, 1576–1582.
 Zhu, K., Dunner Jr., K. and McConkey, D.J. (2009) Proteasome inhibitors
activate autophagy as a cytoprotective response in human prostate cancer
 Wei, Y., Pattingre, S., Sinha, S., Bassik, M. and Levine, B. (2008) JNK1-mediated
phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol. Cell
 Du, Y. et al. (2009) An insight into the mechanistic role of p53-mediated
autophagy inductionin response
neurotoxicity. Autophagy 5, 663–675.
 Vousden, K.H. and Ryan, K.M. (2009) P53 and metabolism. Nat. Rev. Cancer 9,
degradation of aggregated
to proteasomal inhibition-induced
V.I. Korolchuk et al./FEBS Letters 584 (2010) 1393–1398
 Kawaguchi, Y., Kovacs, J.J., McLaurin, A., Vance, J.M., Ito, A. and Yao, T.P. (2003) Download full-text
The deacetylase HDAC6 regulates aggresome formation and cell viability in
response to misfolded protein stress. Cell 115, 727–738.
 Hara, T. et al. (2006) Suppression of basal autophagy in neural cells causes
neurodegenerative disease in mice. Nature 441, 885–889.
 Komatsu, M. et al. (2006) Loss of autophagy in the central nervous system
causes neurodegeneration in mice. Nature 441, 880–884.
autophagy and the ubiquitin-proteasome system. Autophagy 5, 862–863.
 Korolchuk, V.I., Mansilla, A., Menzies, F.M. and Rubinsztein, D.C. (2009)
Autophagy inhibition compromises degradation of ubiquitin-proteasome
pathway substrates. Mol. Cell 33, 517–527.
 Qiao, L. and Zhang, J. (2009) Inhibition of lysosomal functions reduces
proteasomal activity. Neurosci. Lett. 456, 15–19.
 Zhao, J., Brault, J.J., Schild, A., Cao, P., Sandri, M., Schiaffino, S., Lecker, S.H. and
Goldberg, A.L. (2007) FoxO3 coordinately activates protein degradation by the
autophagic/lysosomal and proteasomal pathways in atrophying muscle cells.
Cell Metab. 6, 472–483.
V.I. Korolchuk et al./FEBS Letters 584 (2010) 1393–1398