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Molecular chaperones in protein folding and proteostasis

Abstract

Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.

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Figure 1: Competing reactions of protein folding and aggregation.
Figure 2: The HSP70 chaperone cycle.
Figure 3: Folding in the GroEL–GroES chaperonin cage.
Figure 4: ATPase cycle of the HSP90 chaperone system.
Figure 5: Organization of chaperone pathways in the cytosol.
Figure 6: Protein fates in the proteostasis network.

References

  1. Dobson, C. M., Sali, A. & Karplus, M. Protein folding — a perspective from theory and experiment. Angew. Chem. Int. Edn Engl. 37, 868–893 (1998).

    Google Scholar 

  2. Bartlett, A. I. & Radford, S. E. An expanding arsenal of experimental methods yields an explosion of insights into protein folding mechanisms. Nature Struct. Mol. Biol. 16, 582–588 (2009).

    CAS  Google Scholar 

  3. Dunker, A. K., Silman, I., Uversky, V. N. & Sussman, J. L. Function and structure of inherently disordered proteins. Curr. Opin. Struct. Biol. 18, 756–764 (2008).

    CAS  PubMed  Google Scholar 

  4. Powers, E. T., Morimoto, R. I., Dillin, A., Kelly, J. W. & Balch, W. E. Biological and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem. 78, 959–991 (2009).

    CAS  PubMed  Google Scholar 

  5. Morimoto, R. I. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev. 22, 1427–1438 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).

    ADS  CAS  PubMed  Google Scholar 

  7. Hartl, F. U. Molecular chaperones in cellular protein folding. Nature 381, 571–580 (1996).

    ADS  CAS  PubMed  Google Scholar 

  8. Kubelka, J., Hofrichter, J. & Eaton, W. A. The protein folding 'speed limit'. Curr. Opin. Struct. Biol. 14, 76–88 (2004).

    CAS  PubMed  Google Scholar 

  9. Herbst, R., Schafer, U. & Seckler, R. Equilibrium intermediates in the reversible unfolding of firefly (Photinus pyralis) luciferase. J. Biol. Chem. 272, 7099–7105 (1997).

    CAS  PubMed  Google Scholar 

  10. Ellis, R. J. & Minton, A. P. Protein aggregation in crowded environments. Biol. Chem. 387, 485–497 (2006).

    CAS  PubMed  Google Scholar 

  11. Tokuriki, N. & Tawfik, D. S. Chaperonin overexpression promotes genetic variation and enzyme evolution. Nature 459, 668–671 (2009).

    ADS  CAS  PubMed  Google Scholar 

  12. Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998). This seminal study puts forward the idea that chaperones function in buffering the otherwise deleterious consequences of mutations.

    ADS  CAS  Article  PubMed  Google Scholar 

  13. Skach, W. R. Cellular mechanisms of membrane protein folding. Nature Struct. Mol. Biol. 16, 606–612 (2009).

    CAS  Google Scholar 

  14. Kerner, M. J. et al. Proteome-wide analysis of chaperonin-dependent protein folding in Escherichia coli . Cell 122, 209–220 (2005).

    CAS  PubMed  Google Scholar 

  15. Eichner, T., Kalverda, A. P., Thompson, G. S., Homans, S. W. & Radford, S. E. Conformational conversion during amyloid formation at atomic resolution. Mol. Cell 41, 161–172 (2011). This exciting paper describes, at atomic resolution, the structural features of a non-native folding intermediate that are critical for amyloidogenic aggregation.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Chiti, F. & Dobson, C. M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75, 333–366 (2006).

    CAS  PubMed  Google Scholar 

  17. Bolognesi, B. et al. ANS binding reveals common features of cytotoxic amyloid species. ACS Chem. Biol. 5, 735–740 (2010) This paper provides evidence that the exposure of hydrophobic surfaces by oligomeric aggregation intermediates correlates with their toxicity.

    CAS  PubMed  Google Scholar 

  18. Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003).

    ADS  CAS  PubMed  Google Scholar 

  19. Hartl, F. U. & Hayer-Hartl, M. Converging concepts of protein folding in vitro and in vivo . Nature Struct. Mol. Biol. 16, 574–581 (2009).

    CAS  Google Scholar 

  20. Langer, T. et al. Successive action of DnaK, DnaJ and GroEL along the pathway of chaperone-mediated protein folding. Nature 356, 683–689 (1992).

    ADS  CAS  PubMed  Google Scholar 

  21. Frydman, J., Nimmesgern, E., Ohtsuka, K. & Hartl, F. U. Folding of nascent polypeptide chains in a high molecular mass assembly with molecular chaperones. Nature 370, 111–117 (1994).

    ADS  CAS  PubMed  Google Scholar 

  22. Ellis, R. J. Molecular chaperones: assisting assembly in addition to folding. Trends Biochem. Sci. 31, 395–401 (2006).

    CAS  PubMed  Google Scholar 

  23. Liu, C. et al. Coupled chaperone action in folding and assembly of hexadecameric Rubisco. Nature 463, 197–202 (2010).

    ADS  CAS  PubMed  Google Scholar 

  24. Auluck, P. K., Chan, H. Y. E., Trojanowski, J. Q., Lee, V. M. Y. & Bonini, N. M. Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295, 865–868 (2002).

    ADS  CAS  PubMed  Google Scholar 

  25. Mayer, M. P. Gymnastics of molecular chaperones. Mol. Cell 39, 321–331 (2010).

    CAS  PubMed  Google Scholar 

  26. Kampinga, H. H. & Craig, E. A. The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nature Rev. Mol. Cell Biol. 11, 579–592 (2010).

    CAS  Google Scholar 

  27. Arndt, V. et al. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr. Biol. 20, 143–148 (2010).

    CAS  PubMed  Google Scholar 

  28. Rüdiger, S., Buchberger, A. & Bukau, B. Interaction of Hsp70 chaperones with substrates. Nature Struct. Biol. 4, 342–349 (1997). A key paper in understanding how chaperones recognize their substrates.

    PubMed  Google Scholar 

  29. Rousseau, F., Serrano, L. & Schymkowitz, J. W. H. How evolutionary pressure against protein aggregation shaped chaperone specificity. J. Mol. Biol. 355, 1037–1047 (2006).

    CAS  PubMed  Google Scholar 

  30. Sharma, S. K., De los Rios, P., Christen, P., Lustig, A. & Goloubinoff, P. The kinetic parameters and energy cost of the Hsp70 chaperone as a polypeptide unfoldase. Nature Chem. Biol. 6, 914–920 (2010).

    CAS  Google Scholar 

  31. Frydman, J. Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu. Rev. Biochem. 70, 603–647 (2001).

    CAS  PubMed  Google Scholar 

  32. Horwich, A. L. & Fenton, W. A. Chaperonin-mediated protein folding: using a central cavity to kinetically assist polypeptide chain folding. Q. Rev. Biophys. 42, 83–116 (2009).

    CAS  PubMed  Google Scholar 

  33. Fujiwara, K., Ishihama, Y., Nakahigashi, K., Soga, T. & Taguchi, H. A systematic survey of in vivo obligate chaperonin-dependent substrates. EMBO J. 29, 1552–1564 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Raineri, E., Ribeca, P., Serrano, L. & Maier, T. A more precise characterization of chaperonin substrates. Bioinformatics 26, 1685–1689 (2010).

    CAS  PubMed  Google Scholar 

  35. Tartaglia, G. G., Dobson, C. M., Hartl, F. U. & Vendruscolo, M. Physicochemical determinants of chaperone requirements. J. Mol. Biol. 400, 579–588 (2010).

    CAS  PubMed  Google Scholar 

  36. Xu, Z. H., Horwich, A. L. & Sigler, P. B. The crystal structure of the asymmetric GroEL−GroES−(ADP)7 chaperonin complex. Nature 388, 741–749 (1997).

    ADS  CAS  PubMed  Google Scholar 

  37. Brinker, A. et al. Dual function of protein confinement in chaperonin-assisted protein folding. Cell 107, 223–233 (2001).

    CAS  PubMed  Google Scholar 

  38. Tang, Y. C. et al. Structural features of the GroEL−GroES nano-cage required for rapid folding of encapsulated protein. Cell 125, 903–914 (2006).

    CAS  PubMed  Google Scholar 

  39. Chakraborty, K. et al. Chaperonin-catalyzed rescue of kinetically trapped states in protein folding. Cell 142, 112–122 (2010).

    CAS  PubMed  Google Scholar 

  40. Thirumalai, D. & Lorimer, G. H. Chaperonin-mediated protein folding. Annu. Rev. Biophys. Biomol. Struct. 30, 245–269 (2001).

    CAS  PubMed  Google Scholar 

  41. Lin, Z., Madan, D. & Rye, H. S. GroEL stimulates protein folding through forced unfolding. Nature Struct. Mol. Biol. 15, 303–311 (2008).

    CAS  Google Scholar 

  42. Sharma, S. et al. Monitoring protein conformation along the pathway of chaperonin-assisted folding. Cell 133, 142–153 (2008).

    CAS  PubMed  Google Scholar 

  43. Munoz, I. G. et al. Crystal structure of the open conformation of the mammalian chaperonin CCT in complex with tubulin. Nature Struct. Mol. Biol. 18, 14–19 (2011).

    CAS  Google Scholar 

  44. Douglas, N. R. et al. Dual action of ATP hydrolysis couples lid closure to substrate release into the Group II chaperonin chamber. Cell 144, 240–252 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Reissmann, S., Parnot, C., Booth, C. R., Chiu, W. & Frydman, J. Essential function of the built-in lid in the allosteric regulation of eukaryotic and archaeal chaperonins. Nature Struct. Mol. Biol. 14, 432–440 (2007).

    CAS  Google Scholar 

  46. Kitamura, A. et al. Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state. Nature Cell Biol. 8, 1163–1170 (2006).

    CAS  PubMed  Google Scholar 

  47. Behrends, C. et al. Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. Mol. Cell 23, 887–897 (2006).

    CAS  PubMed  Google Scholar 

  48. Tam, S., Geller, R., Spiess, C. & Frydman, J. The chaperonin TRiC controls polyglutamine aggregation and toxicity through subunit-specific interactions. Nature Cell Biol. 8, 1155–1162 (2006).

    CAS  PubMed  Google Scholar 

  49. Taipale, M., Jarosz, D. F. & Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nature Rev. Mol. Cell Biol. 11, 515–528 (2010).

    CAS  Google Scholar 

  50. McClellan, A. J. et al. Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell 131, 121–135 (2007).

    CAS  PubMed  Google Scholar 

  51. Scheufler, C. et al. Structure of TPR domain–peptide complexes: critical elements in the assembly of the Hsp70–Hsp90 multichaperone machine. Cell 101, 199–210 (2000).

    CAS  PubMed  Google Scholar 

  52. Wandinger, S. K., Richter, K. & Buchner, J. The Hsp90 chaperone machinery. J. Biol. Chem. 283, 18473–18477 (2008).

    CAS  PubMed  Google Scholar 

  53. Ali, M. M. U. et al. Crystal structure of an Hsp90–nucleotide–p23/Sba1 closed chaperone complex. Nature 440, 1013–1017 (2006).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shiau, A. K., Harris, S. F., Southworth, D. R. & Agard, D. A. Structural analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements. Cell 127, 329–340 (2006).

    CAS  PubMed  Google Scholar 

  55. Neckers, L. Heat shock protein 90: the cancer chaperone. J. Biosci. 32, 517–530 (2007).

    CAS  PubMed  Google Scholar 

  56. Geller, R., Vignuzzi, M., Andino, R. & Frydman, J. Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance. Genes Dev. 21, 195–205 (2007). This seminal study describes the requirement of HSP90 in viral assembly, outlining a strategy for antiviral treatment based on HSP90 inhibition.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Eichmann, C., Preissler, S., Riek, R. & Deuerling, E. Cotranslational structure acquisition of nascent polypeptides monitored by NMR spectroscopy. Proc. Natl Acad. Sci. USA 107, 9111–9116 (2010).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cabrita, L. D., Hsu, S. T., Launay, H., Dobson, C. M. & Christodoulou, J. Probing ribosome-nascent chain complexes produced in vivo by NMR spectroscopy. Proc. Natl Acad. Sci. USA 106, 22239–22244 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lu, J. L. & Deutsch, C. Folding zones inside the ribosomal exit tunnel. Nature Struct. Mol. Biol. 12, 1123–1129 (2005).

    CAS  Google Scholar 

  60. Woolhead, C. A., McCormick, P. J. & Johnson, A. E. Nascent membrane and secretory proteins differ in FRET-detected folding far inside the ribosome and in their exposure to ribosomal proteins. Cell 116, 725–736 (2004).

    CAS  PubMed  Google Scholar 

  61. O'Brien, E. P., Hsu, S.-T. D., Christodoulou, J., Vendruscolo, M. & Dobson, C. M. Transient tertiary structure formation within the ribosome exit port. J. Am. Chem. Soc. 132, 16928–16937 (2010).

    CAS  PubMed  Google Scholar 

  62. Elcock, A. H. Molecular simulations of cotranslational protein folding: fragment stabilities, folding cooperativity, and trapping in the ribosome. PLoS Comput Biol. 2, e98 (2006).

    ADS  PubMed  PubMed Central  Google Scholar 

  63. Ferbitz, L. et al. Trigger factor in complex with the ribosome forms a molecular cradle for nascent proteins. Nature 431, 590–596 (2004).

    ADS  CAS  PubMed  Google Scholar 

  64. Kaiser, C. M. et al. Real-time observation of trigger factor function on translating ribosomes. Nature 444, 455–460 (2006).

    ADS  CAS  PubMed  Google Scholar 

  65. Brandt, F. et al. The native 3D organization of bacterial polysomes. Cell 136, 261–271 (2009).

    CAS  PubMed  Google Scholar 

  66. Netzer, W. J. & Hartl, F. U. Recombination of protein domains facilitated by co-translational folding in eukaryotes. Nature 388, 343–349 (1997).

    ADS  CAS  PubMed  Google Scholar 

  67. Frydman, J., Erdjument-Bromage, H., Tempst, P. & Hartl, F. U. Co-translational domain folding as the structural basis for the rapid de novo folding of firefly luciferase. Nature Struct. Biol. 6, 697–705 (1999).

    CAS  PubMed  Google Scholar 

  68. Agashe, V. R. et al. Function of trigger factor and DnaK in multidomain protein folding: increase in yield at the expense of folding speed. Cell 117, 199–209 (2004).

    CAS  PubMed  Google Scholar 

  69. Cuellar, J. et al. The structure of CCT–Hsc70NBD suggests a mechanism for Hsp70 delivery of substrates to the chaperonin. Nature Struct. Mol. Biol. 15, 858–864 (2008).

    CAS  Google Scholar 

  70. Zhang, G. & Ignatova, Z. Generic algorithm to predict the speed of translational elongation: implications for protein biogenesis. PLoS ONE 4, e5036 (2009).

    ADS  PubMed  PubMed Central  Google Scholar 

  71. Vabulas, R. M. & Hartl, F. U. Protein synthesis upon acute nutrient restriction relies on proteasome function. Science 310, 1960–1963 (2005).

    ADS  CAS  PubMed  Google Scholar 

  72. Buchberger, A., Bukau, B. & Sommer, T. Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms. Mol. Cell 40, 238–252 (2010).

    CAS  PubMed  Google Scholar 

  73. Vavouri, T., Semple, J. I., Garcia-Verdugo, R. & Lehner, B. Intrinsic protein disorder and interaction promiscuity are widely associated with dosage sensitivity. Cell 138, 198–208 (2009).

    CAS  PubMed  Google Scholar 

  74. Arndt, V., Rogon, C. & Hohfeld, J. To be, or not to be — molecular chaperones in protein degradation. Cell. Mol. Life Sci. 64, 2525–2541 (2007).

    CAS  PubMed  Google Scholar 

  75. Gamerdinger, M. et al. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. EMBO J. 28, 889–901 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Kaganovich, D., Kopito, R. & Frydman, J. Misfolded proteins partition between two distinct quality control compartments. Nature 454, 1088–1095 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  77. Iwata, A., Riley, B. E., Johnston, J. A. & Kopito, R. R. HDAC6 and microtubules are required for autophagic degradation of aggregated huntingtin. J. Biol. Chem. 280, 40282–40292 (2005).

    CAS  PubMed  Google Scholar 

  78. Kopito, R. R. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 10, 524–530 (2000).

    CAS  PubMed  Google Scholar 

  79. Kern, A., Ackermann, B., Clement, A. M., Duerk, H. & Behl, C. HSF1-controlled and age-associated chaperone capacity in neurons and muscle cells of C. elegans . PLoS ONE 5, e8568 (2010).

    ADS  PubMed  PubMed Central  Google Scholar 

  80. David, D. C. et al. Widespread protein aggregation as an inherent part of aging in C. elegans . PLoS Biol. 8, e1000450 (2010).

    PubMed  PubMed Central  Google Scholar 

  81. Demontis, F. & Perrimon, N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143, 813–825 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Morley, J. F. & Morimoto, R. I. Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol. Biol. Cell 15, 657–664 (2004). This pioneering study provides important insight into the relationship between molecular chaperone functions and longevity.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W. & Dillin, A. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604–1610 (2006). An exciting study demonstrating that active disaggregation and the forced formation of large inclusions prevent the accumulation of toxic aggregate species in C. elegans.

    ADS  CAS  PubMed  Google Scholar 

  84. Ben-Zvi, A., Miller, E. A. & Morimoto, R. I. Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc. Natl Acad. Sci. USA 106, 14914–14919 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cohen, E. et al. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139, 1157–1169 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Olzscha, H. et al. Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144, 67–78 (2011). This paper demonstrates the existence of a metastable sub-proteome that is at risk of co-aggregating with amyloid-forming disease proteins.

    CAS  PubMed  Google Scholar 

  87. Xu, J. et al. Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nature Chem. Biol. 7, 285–295 (2011). This interesting study expands the range of diseases promoted by proteostasis deficiency to cancer.

    CAS  Google Scholar 

  88. Bence, N. F., Sampat, R. M. & Kopito, R. R. Impairment of the ubiquitin−proteasome system by protein aggregation. Science 292, 1552–1555 (2001). This key paper demonstrates that protein aggregation can interfere with protein degradation.

    ADS  CAS  PubMed  Google Scholar 

  89. Gidalevitz, T., Ben-Zvi, A., Ho, K. H., Brignull, H. R. & Morimoto, R. I. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311, 1471–1474 (2006).

    ADS  CAS  PubMed  Google Scholar 

  90. Schaffar, G. et al. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol. Cell 15, 95–105 (2004).

    CAS  PubMed  Google Scholar 

  91. Lotz, G. P. et al. Hsp70 and Hsp40 functionally interact with soluble mutant huntingtin oligomers in a classic ATP-dependent reaction cycle. J. Biol. Chem. 285, 38183–38193 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Sittler, A. et al. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. Hum. Mol. Genet. 10, 1307–1315 (2001).

    CAS  PubMed  Google Scholar 

  93. Mu, T. W. et al. Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 134, 769–781 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Lee, B.-H. et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179–184 (2010). This study describes the first drug-like molecule that can activate proteasome function, thus providing a means to enhance the clearance of aberrantly folded proteins.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  95. Jahn, T. R. & Radford, S. E. The Yin and Yang of protein folding. FEBS J. 272, 5962–5970 (2005).

    CAS  PubMed  Google Scholar 

  96. Vabulas, R. M., Raychaudhuri, S., Hayer-Hartl, M. & Hartl, F. U. Protein folding in the cytoplasm and the heat shock response. Cold Spring Harb. Perspect. Biol. 2, a004390 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Ryan, M. T. & Hoogenraad, N. J. Mitochondrial-nuclear communications. Annu. Rev. Biochem. 76, 701–722 (2007).

    CAS  PubMed  Google Scholar 

  98. Haynes, C. M. & Ron, D. The mitochondrial UPR — protecting organelle protein homeostasis. J. Cell Sci. 123, 3849–3855 (2010).

    CAS  PubMed  Google Scholar 

  99. Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).

    ADS  CAS  PubMed  Google Scholar 

  100. Westerheide, S. D., Anckar, J., Stevens, S. M., Jr, Sistonen, L. & Morimoto, R. I. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science 323, 1063–1066 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank W. Balch, A. Dillin, J. Kelly, R. Morimoto and P.Reinhart for discussions about proteostasis, and thank the members of our laboratory for comments on the manuscript. We apologize to all those whose important work could not be cited owing to space limitations.

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Correspondence to F. Ulrich Hartl.

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F.U.H. is a consultant to Proteostasis Therapeutics.

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Hartl, F., Bracher, A. & Hayer-Hartl, M. Molecular chaperones in protein folding and proteostasis. Nature 475, 324–332 (2011). https://doi.org/10.1038/nature10317

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