Design Principles of Protein Biosynthesis-Coupled Quality Control
2012; Elsevier BV; Volume: 23; Issue: 5 Linguagem: Inglês
10.1016/j.devcel.2012.10.012
ISSN1878-1551
AutoresMonica C. Rodrigo-Brenni, Ramanujan S. Hegde,
Tópico(s)Fungal and yeast genetics research
ResumoThe protein biosynthetic machinery, composed of ribosomes, chaperones, and localization factors, is increasingly found to interact directly with factors dedicated to protein degradation. The coupling of these two opposing processes facilitates quality control of nascent polypeptides at each stage of their maturation. Sequential checkpoints maximize the overall fidelity of protein maturation, minimize the exposure of defective products to the bulk cellular environment, and protect organisms from protein misfolding diseases. The protein biosynthetic machinery, composed of ribosomes, chaperones, and localization factors, is increasingly found to interact directly with factors dedicated to protein degradation. The coupling of these two opposing processes facilitates quality control of nascent polypeptides at each stage of their maturation. Sequential checkpoints maximize the overall fidelity of protein maturation, minimize the exposure of defective products to the bulk cellular environment, and protect organisms from protein misfolding diseases. Cells have extensive surveillance systems to detect errors during the biosynthesis of essentially all of its major macromolecules. This includes DNA replication (Reha-Krantz, 2010Reha-Krantz L.J. DNA polymerase proofreading: Multiple roles maintain genome stability.Biochim. Biophys. Acta. 2010; 1804: 1049-1063Crossref PubMed Scopus (35) Google Scholar), transcription (Sydow and Cramer, 2009Sydow J.F. Cramer P. RNA polymerase fidelity and transcriptional proofreading.Curr. Opin. Struct. Biol. 2009; 19: 732-739Crossref PubMed Scopus (44) Google Scholar), translation (Zaher and Green, 2009Zaher H.S. Green R. Fidelity at the molecular level: lessons from protein synthesis.Cell. 2009; 136: 746-762Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar), and maturation of mRNAs (van Hoof and Wagner, 2011van Hoof A. Wagner E.J. A brief survey of mRNA surveillance.Trends Biochem. Sci. 2011; 36: 585-592Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar), tRNAs (Yadavalli and Ibba, 2012Yadavalli S.S. Ibba M. Quality control in aminoacyl-tRNA synthesis its role in translational fidelity.Adv. Protein Chem. Struct. Biol. 2012; 86: 1-43Crossref PubMed Scopus (30) Google Scholar), and proteins (Buchberger et al., 2010Buchberger A. Bukau B. Sommer T. Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms.Mol. Cell. 2010; 40: 238-252Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). Each of these biosynthetic processes has intrinsic limits on overall fidelity, resulting in a low but tangible rate of errors. In addition to biosynthetic errors, environmental insults such as ionizing radiation, reactive oxygen species, and temperature fluctuations result in damage to cellular macromolecules. Cells therefore face a constant barrage of defective or damaged macromolecules that, if left unresolved, have the potential to disrupt cellular homeostasis, reduce fitness, cause disease, and contribute to aging. Thus, there is a strong selective pressure to detect defective macromolecules and either correct or dispose of them. The potentially disruptive nature of defective macromolecules places a premium on early detection and rapid resolution. This explains why many quality control processes have evolved to act at the site of biosynthesis, before an erroneous product is released and can engage downstream cellular pathways. The most obvious examples include internal proofreading by DNA polymerases (Reha-Krantz, 2010Reha-Krantz L.J. DNA polymerase proofreading: Multiple roles maintain genome stability.Biochim. Biophys. Acta. 2010; 1804: 1049-1063Crossref PubMed Scopus (35) Google Scholar) and kinetic proofreading during translation (Zaher and Green, 2009Zaher H.S. Green R. Fidelity at the molecular level: lessons from protein synthesis.Cell. 2009; 136: 746-762Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). Less obvious is the exploitation of compartments, such as the nucleus and endoplasmic reticulum (ER), for maturation of nascent RNAs and proteins in a protected environment before their regulated trafficking to their site of function. These early-acting quality control systems coexist with partially redundant downstream mechanisms. For example, proofreading mechanisms during replication are complementary to DNA mismatch repair that deal with errors after they have occurred. Similarly, fidelity of decoding during translation is combined with postsynthesis quality control of misfolded proteins to avoid defects. Thus, numerous quality control mechanisms leading from DNA to functional protein each make unique, overlapping contributions to minimize the error rate of this complex process. The physiologic relevance of each contribution is evidenced by the numerous protein misfolding and neurodegenerative diseases that result when these quality control processes fail (Balch et al., 2008Balch W.E. Morimoto R.I. Dillin A. Kelly J.W. Adapting proteostasis for disease intervention.Science. 2008; 319: 916-919Crossref PubMed Scopus (710) Google Scholar). In this Review, we examine the concept of biosynthesis-coupled quality control during protein maturation. After a brief historical perspective on the initial development of this field, we discuss several examples of interactions between various biosynthetic machinery and degradation factors. This includes interactions between ribosomes, targeting factors, and chaperones with the ubiquitin-proteasome system. Although the relevance of some of these interactions for quality control is not fully established, their consideration at this juncture is nevertheless worthwhile for providing a conceptual framework for this emerging area and highlighting key questions for future research. Nascent proteins must fold into their final three-dimensional form and in many cases must be modified, assembled with partners, and localized to specific locations in order to function. If these processes fail, the affected protein must be recognized and degraded. How this critical triage decision is made has been a central question in the field of quality control for over 20 years. One of the earliest mechanisms of triage, kinetic partitioning, emerged from studies in bacterial systems (Wickner et al., 1999Wickner S. Maurizi M.R. Gottesman S. Posttranslational quality control: folding, refolding, and degrading proteins.Science. 1999; 286: 1888-1893Crossref PubMed Scopus (720) Google Scholar). In this view, newly synthesized polypeptides released from the ribosome partition between chaperones and proteases, both capable of recognizing nonnative proteins. Cycles of chaperone binding and release would provide an opportunity to fold, while partitioning to proteases leads to the irreversible fate of degradation (Figure 1A). Given that the major classes of chaperones and proteases in bacteria do not interact with each other, partitioning seems to be the primary strategy for quality control in bacteria. Although partitioning was initially postulated to apply to eukaryotes as well, two sets of observations led to a qualitatively different concept for quality control. The first concerned the nature of the degradation system in eukaryotes (Hershko and Ciechanover, 1998Hershko A. Ciechanover A. The ubiquitin system.Annu. Rev. Biochem. 1998; 67: 425-479Crossref PubMed Scopus (4646) Google Scholar). Quality control in both the cytosol and ER were found to typically culminate at the proteasome (Buchberger et al., 2010Buchberger A. Bukau B. Sommer T. Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms.Mol. Cell. 2010; 40: 238-252Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). Commitment to proteasomal degradation normally relies on ubiquitin ligases to tag clients with a polyubiquitin chain. However, the ligases often do not recognize their clients per se, but rely on adaptors that bring a subset of cellular proteins in proximity to the ligase. Specificity of degradation is therefore imparted by the ligase in conjunction with any associated adaptor(s) (Deshaies and Joazeiro, 2009Deshaies R.J. Joazeiro C.A. RING domain E3 ubiquitin ligases.Annu. Rev. Biochem. 2009; 78: 399-434Crossref PubMed Scopus (709) Google Scholar). The second key observation was the discovery that the major cytosolic chaperone Hsp70 can interact directly with a ubiquitin ligase (Ballinger et al., 1999Ballinger C.A. Connell P. Wu Y. Hu Z. Thompson L.J. Yin L.Y. Patterson C. Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions.Mol. Cell. Biol. 1999; 19: 4535-4545Crossref PubMed Google Scholar). This immediately suggested that chaperones might serve as adaptors that permit certain ubiquitin ligases to recognize nonnative proteins (Connell et al., 2001Connell P. Ballinger C.A. Jiang J. Wu Y. Thompson L.J. Höhfeld J. Patterson C. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins.Nat. Cell Biol. 2001; 3: 93-96Crossref PubMed Scopus (0) Google Scholar; Höhfeld et al., 2001Höhfeld J. Cyr D.M. Patterson C. From the cradle to the grave: molecular chaperones that may choose between folding and degradation.EMBO Rep. 2001; 2: 885-890Crossref PubMed Scopus (207) Google Scholar; Meacham et al., 2001Meacham G.C. Patterson C. Zhang W. Younger J.M. Cyr D.M. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation.Nat. Cell Biol. 2001; 3: 100-105Crossref PubMed Scopus (499) Google Scholar). Some time later, chaperones in the ER such as BiP, PDI family members, and GRP94 were also found to interact with components of ubiquitin ligase complexes involved in ER-associated degradation (Bernardi et al., 2008Bernardi K.M. Forster M.L. Lencer W.I. Tsai B. Derlin-1 facilitates the retro-translocation of cholera toxin.Mol. Biol. Cell. 2008; 19: 877-884Crossref PubMed Scopus (66) Google Scholar; Christianson et al., 2008Christianson J.C. Shaler T.A. Tyler R.E. Kopito R.R. OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD.Nat. Cell Biol. 2008; 10: 272-282Crossref PubMed Scopus (199) Google Scholar; Denic et al., 2006Denic V. Quan E.M. Weissman J.S. A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation.Cell. 2006; 126: 349-359Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar; Hosokawa et al., 2008Hosokawa N. Wada I. Nagasawa K. Moriyama T. Okawa K. Nagata K. Human XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L ubiquitin ligase complex and BiP.J. Biol. Chem. 2008; 283: 20914-20924Crossref PubMed Scopus (79) Google Scholar). These observations implied that nascent eukaryotic proteins did not passively partition between the folding and degradation machinery as seen in bacteria. Instead, the two pathways seemed to be more intimately linked, with quality control relying on an active role for chaperones in delivering nonnative proteins to degradation factors (Figure 1B). The best-studied class of chaperones that links protein folding to degradation is the Hsp70 family of ATPases (Mayer and Bukau, 2005Mayer M.P. Bukau B. Hsp70 chaperones: cellular functions and molecular mechanism.Cell. Mol. Life Sci. 2005; 62: 670-684Crossref PubMed Scopus (863) Google Scholar). The ATP-bound state of Hsp70s has a low affinity for substrate, favoring dynamic binding and release. By contrast, the ADP-bound state has a high affinity for substrates, thereby binding and shielding the client. A wide range of interacting partners (often termed cochaperones) have been described that regulate the activity of Hsp70s (Kampinga and Craig, 2010Kampinga H.H. Craig E.A. The HSP70 chaperone machinery: J proteins as drivers of functional specificity.Nat. Rev. Mol. Cell Biol. 2010; 11: 579-592Crossref PubMed Scopus (285) Google Scholar). These include J-domain family members that typically stimulate ATPase activity, nucleotide exchange factors that drive ADP replacement by ATP, factors that recruit Hsp70 to specific cellular locations, and ubiquitin ligases. Furthermore, the Hsp70 system can function together with other chaperones via their linking by organizing factors. For example, Hop is a two TPR domain protein that juxtaposes Hsp70 and Hsp90 via their C-terminal tails to facilitate folding of certain substrates. Thus, based on the associated factors, the basic Hsp70 module can be co-opted for a wide range of functions ranging from protein folding, protein complex assembly and dissociation, protein targeting, protein translocation, and protein degradation. A key advance in understanding the role of Hsp70 in degradation came with the discovery that its C terminus associates with the ubiquitin ligase CHIP (Ballinger et al., 1999Ballinger C.A. Connell P. Wu Y. Hu Z. Thompson L.J. Yin L.Y. Patterson C. Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions.Mol. Cell. Biol. 1999; 19: 4535-4545Crossref PubMed Google Scholar). This suggested that clients with prolonged Hsp70 interaction would eventually be ubiquitinated, thereby effecting quality control of folding-defective proteins (Connell et al., 2001Connell P. Ballinger C.A. Jiang J. Wu Y. Thompson L.J. Höhfeld J. Patterson C. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins.Nat. Cell Biol. 2001; 3: 93-96Crossref PubMed Scopus (0) Google Scholar; Meacham et al., 2001Meacham G.C. Patterson C. Zhang W. Younger J.M. Cyr D.M. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation.Nat. Cell Biol. 2001; 3: 100-105Crossref PubMed Scopus (499) Google Scholar). Subsequent studies of Hsp70 interaction partners identified additional links to degradation pathways including other ubiquitin ligases, the proteasome, and autophagy factors (Esser et al., 2004Esser C. Alberti S. Höhfeld J. Cooperation of molecular chaperones with the ubiquitin/proteasome system.Biochim. Biophys. Acta. 2004; 1695: 171-188Crossref PubMed Scopus (119) Google Scholar; Arndt et al., 2007Arndt V. Rogon C. Höhfeld J. To be, or not to be—molecular chaperones in protein degradation.Cell. Mol. Life Sci. 2007; 64: 2525-2541Crossref PubMed Scopus (68) Google Scholar; Gamerdinger et al., 2011Gamerdinger M. Carra S. Behl C. Emerging roles of molecular chaperones and co-chaperones in selective autophagy: focus on BAG proteins.J. Mol. Med. 2011; 89: 1175-1182Crossref PubMed Scopus (21) Google Scholar). Two illustrative examples are the J-domain protein HSJ1 and the nucleotide exchange factor Bag1. HSJ1, like many J-proteins, stimulates the ATPase activity of Hsp70 to favor substrate binding (Cheetham et al., 1994Cheetham M.E. Jackson A.P. Anderton B.H. Regulation of 70-kDa heat-shock-protein ATPase activity and substrate binding by human DnaJ-like proteins, HSJ1a and HSJ1b.Eur. J. Biochem. 1994; 226: 99-107Crossref PubMed Scopus (58) Google Scholar). Importantly, however, it also contains ubiquitin interacting motifs (UIM) that bind to mono- and polyubiquitin (Chapple et al., 2004Chapple J.P. van der Spuy J. Poopalasundaram S. Cheetham M.E. Neuronal DnaJ proteins HSJ1a and HSJ1b: a role in linking the Hsp70 chaperone machine to the ubiquitin-proteasome system?.Biochem. Soc. Trans. 2004; 32: 640-642Crossref PubMed Scopus (20) Google Scholar; Howarth et al., 2007Howarth J.L. Kelly S. Keasey M.P. Glover C.P. Lee Y.B. Mitrophanous K. Chapple J.P. Gallo J.M. Cheetham M.E. Uney J.B. Hsp40 molecules that target to the ubiquitin-proteasome system decrease inclusion formation in models of polyglutamine disease.Mol. Ther. 2007; 15: 1100-1105PubMed Google Scholar; Westhoff et al., 2005Westhoff B. Chapple J.P. van der Spuy J. Höhfeld J. Cheetham M.E. HSJ1 is a neuronal shuttling factor for the sorting of chaperone clients to the proteasome.Curr. Biol. 2005; 15: 1058-1064Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). This suggests that ubiquitinated clients on Hsp70 would preferentially recruit HSJ1 via a bipartite interaction with both the chaperone (via the J-domain) and ubiquitin (via the UIM domain). ATP hydrolysis stimulated by the J-domain would then stabilize this complex. Bag1, on the other hand, is an exchange factor (Briknarová et al., 2001Briknarová K. Takayama S. Brive L. Havert M.L. Knee D.A. Velasco J. Homma S. Cabezas E. Stuart J. Hoyt D.W. et al.Structural analysis of BAG1 cochaperone and its interactions with Hsc70 heat shock protein.Nat. Struct. Biol. 2001; 8: 349-352Crossref PubMed Scopus (90) Google Scholar; Höhfeld and Jentsch, 1997Höhfeld J. Jentsch S. GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1.EMBO J. 1997; 16: 6209-6216Crossref PubMed Scopus (284) Google Scholar; Takayama et al., 1997Takayama S. Bimston D.N. Matsuzawa S. Freeman B.C. Aime-Sempe C. Xie Z. Morimoto R.I. Reed J.C. BAG-1 modulates the chaperone activity of Hsp70/Hsc70.EMBO J. 1997; 16: 4887-4896Crossref PubMed Scopus (366) Google Scholar) that can associate with the proteasome via a ubiquitin-like (Ubl) domain (Lüders et al., 2000Lüders J. Demand J. Höhfeld J. The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome.J. Biol. Chem. 2000; 275: 4613-4617Crossref PubMed Scopus (277) Google Scholar). It is therefore plausible that proteasome-bound Bag1 would recruit Hsp70 complexed with a ubiquitinated client. Because proteasomes also contain ubiquitin receptors (Finley, 2009Finley D. Recognition and processing of ubiquitin-protein conjugates by the proteasome.Annu. Rev. Biochem. 2009; 78: 477-513Crossref PubMed Scopus (524) Google Scholar), recruitment could involve a bipartite interaction, with both Hsp70 and ubiquitin contributing to the avidity. Once recruited, the Bag domain would stimulate nucleotide exchange to induce release of the substrate, which could then be captured in an unfolded state by the proteasome. Thus, via the sequential actions of CHIP, HSJ1, Bag1, and the proteasome, an Hsp70-bound client could be routed for degradation in a highly regulated manner without release from the chaperone (Figure 2). Although this is an attractive scheme and the individual activities of the factors have been documented, their concerted sequential action as described above remains to be firmly established. Furthermore, the situation is considerably more complex because of the concurrent presence of dozens of competing factors (Arndt et al., 2007Arndt V. Rogon C. Höhfeld J. To be, or not to be—molecular chaperones in protein degradation.Cell. Mol. Life Sci. 2007; 64: 2525-2541Crossref PubMed Scopus (68) Google Scholar; Esser et al., 2004Esser C. Alberti S. Höhfeld J. Cooperation of molecular chaperones with the ubiquitin/proteasome system.Biochim. Biophys. Acta. 2004; 1695: 171-188Crossref PubMed Scopus (119) Google Scholar; Gamerdinger et al., 2011Gamerdinger M. Carra S. Behl C. Emerging roles of molecular chaperones and co-chaperones in selective autophagy: focus on BAG proteins.J. Mol. Med. 2011; 89: 1175-1182Crossref PubMed Scopus (21) Google Scholar) including other J-proteins and Bag proteins (Kampinga and Craig, 2010Kampinga H.H. Craig E.A. The HSP70 chaperone machinery: J proteins as drivers of functional specificity.Nat. Rev. Mol. Cell Biol. 2010; 11: 579-592Crossref PubMed Scopus (285) Google Scholar; Takayama et al., 1999Takayama S. Xie Z. Reed J.C. An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators.J. Biol. Chem. 1999; 274: 781-786Crossref PubMed Scopus (267) Google Scholar), factors like HOP that would compete with CHIP for Hsp70 binding (Muller et al., 2012Muller P. Ruckova E. Halada P. Coates P.J. Hrstka R. Lane D.P. Vojtesek B. C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances.Oncogene. 2012; Google Scholar), and the fact that CHIP can ubiquitinate not only clients (Murata et al., 2001Murata S. Minami Y. Minami M. Chiba T. Tanaka K. CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein.EMBO Rep. 2001; 2: 1133-1138Crossref PubMed Scopus (288) Google Scholar; Younger et al., 2004Younger J.M. Ren H.Y. Chen L. Fan C.Y. Fields A. Patterson C. Cyr D.M. A foldable CFTRDeltaF508 biogenic intermediate accumulates upon inhibition of the Hsc70-CHIP E3 ubiquitin ligase.J. Cell Biol. 2004; 167: 1075-1085Crossref PubMed Scopus (96) Google Scholar), but also Hsp70 and Bag proteins (Alberti et al., 2002Alberti S. Demand J. Esser C. Emmerich N. Schild H. Hohfeld J. Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome.J. Biol. Chem. 2002; 277: 45920-45927Crossref PubMed Scopus (113) Google Scholar; Jiang et al., 2001Jiang J. Ballinger C.A. Wu Y. Dai Q. Cyr D.M. Höhfeld J. Patterson C. CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation.J. Biol. Chem. 2001; 276: 42938-42944Crossref PubMed Scopus (333) Google Scholar). Thus, the actual events that determine when a folding attempt should be aborted, and how the ubiquitinated product is delivered to the proteasome, remain to be elucidated. Nevertheless, the above possible scenario highlights the key events that need to occur to efficiently target a chaperone-bound protein for degradation (Figure 2). First, a profolding complex composed of Hsp70, a J-protein, a nucleotide exchange factor (NEF), and perhaps other chaperones, must be remodeled into a prodegradation complex that includes a ubiquitin ligase (Arndt et al., 2007Arndt V. Rogon C. Höhfeld J. To be, or not to be—molecular chaperones in protein degradation.Cell. Mol. Life Sci. 2007; 64: 2525-2541Crossref PubMed Scopus (68) Google Scholar; Esser et al., 2004Esser C. Alberti S. Höhfeld J. Cooperation of molecular chaperones with the ubiquitin/proteasome system.Biochim. Biophys. Acta. 2004; 1695: 171-188Crossref PubMed Scopus (119) Google Scholar; McClellan et al., 2005McClellan A.J. Scott M.D. Frydman J. Folding and quality control of the VHL tumor suppressor proceed through distinct chaperone pathways.Cell. 2005; 121: 739-748Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar; Muller et al., 2012Muller P. Ruckova E. Halada P. Coates P.J. Hrstka R. Lane D.P. Vojtesek B. C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances.Oncogene. 2012; Google Scholar). Due to the dynamic nature of the various cofactor interactions with Hsp70, remodeling is presumably a reversible process. Whether the timing of remodeling is stochastic, regulated, or in some manner coupled to the number of prior folding attempts remains unknown. However, the precise timing of the switch from a folding to a degradation pathway is critical to determining overall efficiency of protein maturation, risk of aggregation, and half-life. Mechanistic insight into this key step remains a vexing problem that merits scrutiny. Once the ubiquitin ligase becomes part of the chaperone complex, the client is polyubiquitinated (Connell et al., 2001Connell P. Ballinger C.A. Jiang J. Wu Y. Thompson L.J. Höhfeld J. Patterson C. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins.Nat. Cell Biol. 2001; 3: 93-96Crossref PubMed Scopus (0) Google Scholar; Meacham et al., 2001Meacham G.C. Patterson C. Zhang W. Younger J.M. Cyr D.M. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation.Nat. Cell Biol. 2001; 3: 100-105Crossref PubMed Scopus (499) Google Scholar; Stankiewicz et al., 2010Stankiewicz M. Nikolay R. Rybin V. Mayer M.P. CHIP participates in protein triage decisions by preferentially ubiquitinating Hsp70-bound substrates.FEBS J. 2010; 277: 3353-3367Crossref PubMed Scopus (18) Google Scholar) in what is presumably the committed step in degradation. The complex of Hsp70 with ubiquitinated substrate therefore represents a “targeting complex” with the destination being the proteasome. In most protein targeting reactions, a committed targeting complex is typically stabilized until its regulated disassembly at the destination (Shan and Walter, 2005Shan S.O. Walter P. Co-translational protein targeting by the signal recognition particle.FEBS Lett. 2005; 579: 921-926Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). It is therefore logical to posit that commitment to degradation is accompanied by a shift in Hsp70 activity from dynamic to stable client binding. This would ensure sequestration of the misfolded substrate until its delivery to the proteasome and avoid trying to “fold” or otherwise release a committed degradation substrate. How complex stabilization is achieved is unclear, but could be via recruitment of a specific J-domain (as postulated above), exploitation of the peptide binding capacity of CHIP itself (Rosser et al., 2007Rosser M.F. Washburn E. Muchowski P.J. Patterson C. Cyr D.M. Chaperone functions of the E3 ubiquitin ligase CHIP.J. Biol. Chem. 2007; 282: 22267-22277Crossref PubMed Scopus (68) Google Scholar), or some other mechanism. Targeting of chaperone-bound clients to the proteasome could be mediated by ubiquitin receptors on the proteasome, potentially with the aid of factors (such as Bag1) that bridge the chaperone and proteasome. Following delivery, the targeting complex should be disassembled to release the substrate for degradation and recycle the factors for another round. By analogy to other targeting reactions, complex disassembly should be selectively stimulated at the destination. Thus, it is attractive to posit that dissociation of chaperone-client complexes is coupled in some manner to proteasome delivery. This key reaction remains to be studied. Analogous reactions would presumably need to occur in the ER lumen during quality control. The most directly related from a mechanistic point of view is presumably BiP, the ER-lumenal Hsp70 family member. Like its cytosolic counterpart, BiP engages nascent proteins early in their biogenesis at the translocon (Zimmermann, 1998Zimmermann R. The role of molecular chaperones in protein transport into the mammalian endoplasmic reticulum.Biol. Chem. 1998; 379: 275-282PubMed Google Scholar) and subsequently participates in their folding (Simons et al., 1995Simons J.F. Ferro-Novick S. Rose M.D. Helenius A. BiP/Kar2p serves as a molecular chaperone during carboxypeptidase Y folding in yeast.J. Cell Biol. 1995; 130: 41-49Crossref PubMed Scopus (143) Google Scholar). If folding is unsuccessful, BiP-associated clients are triaged for degradation via targeting to a ubiquitin ligase-containing dislocation apparatus (Mehnert et al., 2010Mehnert M. Sommer T. Jarosch E. ERAD ubiquitin ligases: multifunctional tools for protein quality control and waste disposal in the endoplasmic reticulum.Bioessays. 2010; 32: 905-913Crossref PubMed Scopus (30) Google Scholar) that exports proteins from the ER to the cytosol (Hampton and Sommer, 2012Hampton R.Y. Sommer T. Finding the will and the way of ERAD substrate retrotranslocation.Curr. Opin. Cell Biol. 2012; 24: 460-466Crossref PubMed Scopus (35) Google Scholar). BiP’s role in these processes is regulated by its interacting partners that include various J-domain proteins, NEFs, chaperones, and adaptors (Otero et al., 2010Otero J.H. Lizák B. Hendershot L.M. Life and death of a BiP substrate.Semin. Cell Dev. Biol. 2010; 21: 472-478Crossref PubMed Scopus (48) Google Scholar). Thus, as in the cytosol, BiP-mediated quality control in the ER is likely to involve a number of cofactors that enable BiP to be used during both biosynthetic and degradation pathways (Otero et al., 2010Otero J.H. Lizák B. Hendershot L.M. Life and death of a BiP substrate.Semin. Cell Dev. Biol. 2010; 21: 472-478Crossref PubMed Scopus (48) Google Scholar; Vembar et al., 2010Vembar S.S. Jonikas M.C. Hendershot L.M. Weissman J.S. Brodsky J.L. J domain co-chaperone specificity defines the role of BiP during protein translocation.J. Biol. Chem. 2010; 285: 22484-22494Crossref PubMed Scopus (19) Google Scholar). However, the coordination of these various cofactor activities to properly regulate these two opposing activities remains unclear. Although less well studied, other classes of chaperones are also similarly linked to degradation machinery. These include Hsp90 in the cytosol (Connell et al., 2001Connell P. Ballinger C.A. Jiang J. Wu Y. Thompson L.J. Höhfeld J. Patterson C. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins.Nat. Cell Biol. 2001; 3: 93-96Crossref PubMed Scopus (0) Google Scholar) and PDI (Bernardi et al., 2008Bernardi K.M. Forster M.L. Lencer W.I. Tsai B. Derlin-1 facilitates the retro-translocation of cholera toxin.Mol. Biol. Cell. 2008; 19: 877-884Crossref PubMed Scopus (66) Google Scholar), GRP94 (Christianson et al., 2008Christianson J.C. Shaler T.A. Tyler R.E. Kopito R.R. OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD.Nat. Cell Biol. 2008; 10: 272-282Crossref PubMed Scopus (199) Google Scholar), and calnexin (Oda et al., 2003Oda Y. Hosokawa N. Wada I. Nagata K. EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin.Science. 2003; 299: 1394-1397Crossref PubMed Scopus (299) Google Scholar) in the ER lumen. Although a detailed discussion of their known interacting partners is beyond the scope of this review, it suffices to note that each of them can interact with factors whose main function is to effect degradation. The repeated emergence of this theme in otherwise unrelated chapero
Referência(s)