Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Protein homeostasis: live long, won't prosper

Nature Reviews Molecular Cell Biology volume 14, pages 55–61 (2013)Cite this article

Subjects

Abstract

Protein turnover is an effective way of maintaining a functional proteome, as old and potentially damaged polypeptides are destroyed and replaced by newly synthesized copies. An increasing number of intracellular proteins, however, have been identified that evade this turnover process and instead are maintained over a cell's lifetime. This diverse group of long-lived proteins might be particularly prone to accumulation of damage and thus have a crucial role in the functional deterioration of key regulatory processes during ageing.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Long-lived proteins and the accumulation of damage.
Figure 2: Crystallin is a long-lived lens protein important for eye function.
Figure 3: Specific components of the NPC are long-lived.

Similar content being viewed by others

References

  1. Steinkraus, K. A., Kaeberlein, M. & Kennedy, B. K. Replicative aging in yeast: the means to the end. Annu. Rev. Cell Dev. Biol. 24, 29–54 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Taylor, R. C. & Dillin, A. Aging as an event of proteostasis collapse. Cold Spring Harb. Perspect. Biol. 3, a004440 (2011).

    PubMed  PubMed Central  Google Scholar 

  3. D'Angelo, M. A., Raices, M., Panowski, S. H. & Hetzer, M. W. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell 136, 284–295 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Savas, J. N. et al. Extremely long-lived nuclear pore proteins in the rat brain. Science 335, 942 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Belle, A., Tanay, A., Bitincka, L., Shamir, R. & O'Shea, E. K. Quantification of protein half-lives in the budding yeast proteome. Proc. Natl Acad. Sci. USA 103, 13004–13009 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Cambridge, S. B. et al. Systems-wide proteomic analysis in mammalian cells reveals conserved, functional protein turnover. J. Proteome Res. 10, 5275–5284 (2011).

    CAS  PubMed  Google Scholar 

  7. Yen, H. C., Xu, Q., Chou, D. M., Zhao, Z. & Elledge, S. J. Global protein stability profiling in mammalian cells. Science 322, 918–923 (2008).

    CAS  PubMed  Google Scholar 

  8. Price, J. C., Guan, S., Burlingame, A., Prusiner, S. B. & Ghaemmaghami, S. Analysis of proteome dynamics in the mouse brain. Proc. Natl Acad. Sci. USA 107, 14508–14513 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Piha, R. S., Cuenod, M. & Waelsch, H. Metabolism of histones of brain and liver. J. Biol. Chem. 241, 2397–2404 (1966).

    CAS  PubMed  Google Scholar 

  10. Fischer, C. A. & Morell, P. Turnover of proteins in myelin and myelin-like material of mouse brain. Brain Res. 74, 51–65 (1974).

    CAS  PubMed  Google Scholar 

  11. Rodriguez de Lores, A., Alberici de Canal, M. & De Robertis, E. Turnover of proteins in subcellular fractions of rat cerebral cortex. Brain Res. 31, 179–184 (1971).

    Google Scholar 

  12. Verzijl, N. et al. Effect of collagen turnover on the accumulation of advanced glycation end products. J. Biol. Chem. 275, 39027–39031 (2000).

    CAS  PubMed  Google Scholar 

  13. Sell, D. R. & Monnier, V. M. Aging of long-lived proteins: extracellular matrix (collagens, elastins, proteoglycans) and lens crystallins. in Comprehensive Physiology 235–305 (John Wiley & Sons, 2011).

    Google Scholar 

  14. Shapiro, S. D., Endicott, S. K., Province, M. A., Pierce, J. A. & Campbell, E. J. Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. J. Clin. Invest. 87, 1828–1834 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Masters, P. M., Bada, J. L. & Zigler, J. S. Jr. Aspartic acid racemisation in the human lens during ageing and in cataract formation. Nature 268, 71–73 (1977).

    CAS  PubMed  Google Scholar 

  16. Helfman, P. M. & Bada, J. L. Aspartic acid racemization in tooth enamel from living humans. Proc. Natl Acad. Sci. USA 72, 2891–2894 (1975).

    Google Scholar 

  17. Helfman, P. M. & Bada, J. L. Aspartic acid racemisation in dentine as a measure of ageing. Nature 262, 279–281 (1976).

    CAS  PubMed  Google Scholar 

  18. Tachibana-Konwalski, K. et al. Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes. Genes Dev. 24, 2505–2516 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. McClatchy, D. B., Dong, M. Q., Wu, C. C., Venable, J. D. & Yates, J. R. 15N metabolic labeling of mammalian tissue with slow protein turnover. J. Proteome Res. 6, 2005–2010 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bloemendal, H. The vertebrate eye lens. Science 197, 127–138 (1977).

    CAS  PubMed  Google Scholar 

  21. Graw, J. Genetics of crystallins: cataract and beyond. Exp. Eye Res. 88, 173–189 (2009).

    CAS  PubMed  Google Scholar 

  22. Wride, M. A. Lens fibre cell differentiation and organelle loss: many paths lead to clarity. Phil. Trans. R. Soc. B 366, 1219–1233 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Bassnett, S. Lens organelle degradation. Exp. Eye Res. 74, 1–6 (2002).

    CAS  PubMed  Google Scholar 

  24. Bassnett, S., Shi, Y. & Vrensen, G. F. Biological glass: structural determinants of eye lens transparency. Phil. Trans. R. Soc. B 366, 1250–1264 (2011).

    PubMed  PubMed Central  Google Scholar 

  25. Horwitz, J. α-crystallin can function as a molecular chaperone. Proc. Natl Acad. Sci. USA 89, 10449–10453 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Rao, P. V., Huang, Q. L., Horwitz, J. & Zigler, J. S. Jr. Evidence that α-crystallin prevents non-specific protein aggregation in the intact eye lens. Biochim. Biophys. Acta 1245, 439–447 (1995).

    PubMed  Google Scholar 

  27. Xi, J. H. et al. Mechanism of small heat shock protein function in vivo: a knock-in mouse model demonstrates that the R49C mutation in αA-crystallin enhances protein insolubility and cell death. J. Biol. Chem. 283, 5801–5814 (2008).

    CAS  PubMed  Google Scholar 

  28. Giblin, F. J. Glutathione: a vital lens antioxidant. J. Ocul. Pharmacol. Ther. 16, 121–135 (2000).

    CAS  PubMed  Google Scholar 

  29. Lou, M. F. Redox regulation in the lens. Prog. Retin. Eye Res. 22, 657–682 (2003).

    CAS  PubMed  Google Scholar 

  30. Xing, K. Y. & Lou, M. F. Effect of age on the thioltransferase (glutaredoxin) and thioredoxin systems in the human lens. Invest. Ophthalmol. Vis. Sci. 51, 6598–6604 (2010).

    PubMed  PubMed Central  Google Scholar 

  31. Sharma, K. K. & Ortwerth, B. J. Effect of cross-linking on the chaperone-like function of α-crystallin. Exp. Eye Res. 61, 413–421 (1995).

    CAS  PubMed  Google Scholar 

  32. Gupta, R. & Srivastava, O. P. Deamidation affects structural and functional properties of human αA-crystallin and its oligomerization with αB-crystallin. J. Biol. Chem. 279, 44258–44269 (2004).

    CAS  PubMed  Google Scholar 

  33. Harding, J. J. Free and protein-bound glutathione in normal and cataractous human lenses. Biochem. J. 117, 957–960 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sharma, K. K. & Santhoshkumar, P. Lens aging: effects of crystallins. Biochim. Biophys. Acta 1790, 1095–1108 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hanson, S. R., Hasan, A., Smith, D. L. & Smith, J. B. The major in vivo modifications of the human water-insoluble lens crystallins are disulfide bonds, deamidation, methionine oxidation and backbone cleavage. Exp. Eye Res. 71, 195–207 (2000).

    CAS  PubMed  Google Scholar 

  36. Ortwerth, B. J. & Olesen, P. R. Studies on the solubilization of the water-insoluble fraction from human lens and cataract. Exp. Eye Res. 55, 777–783 (1992).

    CAS  PubMed  Google Scholar 

  37. Ahmed, N. et al. Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins. Invest. Ophthalmol. Vis. Sci. 44, 5287–5292 (2003).

    PubMed  Google Scholar 

  38. Takemoto, L. J. Quantitation of asparagine-101 deamidation from αA crystallin during aging of the human lens. Curr. Eye Res. 17, 247–250 (1998).

    CAS  PubMed  Google Scholar 

  39. Wilmarth, P. A. et al. Age-related changes in human crystallins determined from comparative analysis of post-translational modifications in young and aged lens: does deamidation contribute to crystallin insolubility? J. Proteome Res. 5, 2554–2566 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Bloemendal, H. et al. Ageing and vision: structure, stability and function of lens crystallins. Prog. Biophys. Mol. Biol. 86, 407–485 (2004).

    CAS  PubMed  Google Scholar 

  41. Roy, D. & Spector, A. Absence of low-molecular-weight α-crystallin in nuclear region of old human lenses. Proc. Natl Acad. Sci. USA 73, 3484–3487 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kerrigan, J. J., Mansell, J. P. & Sandy, J. R. Matrix turnover. J. Orthod. 27, 227–233 (2000).

    CAS  PubMed  Google Scholar 

  43. Braverman, I. M. & Fonferko, E. Studies in cutaneous aging: I. The elastic fiber network. J. Invest. Dermatol. 78, 434–443 (1982).

    CAS  PubMed  Google Scholar 

  44. Kragstrup, T. W., Kjaer, M. & Mackey, A. L. Structural, biochemical, cellular, and functional changes in skeletal muscle extracellular matrix with aging. Scand. J. Med. Sci. Sports 21, 749–757 (2011).

    CAS  PubMed  Google Scholar 

  45. Sell, D. R. & Monnier, V. M. Molecular basis of arterial stiffening: role of glycation — a mini-review. Gerontology 58, 227–237 (2012).

    CAS  PubMed  Google Scholar 

  46. Fonck, E. et al. Effect of aging on elastin functionality in human cerebral arteries. Stroke 40, 2552–2556 (2009).

    CAS  PubMed  Google Scholar 

  47. Gosselin, L. E., Adams, C., Cotter, T. A., McCormick, R. J. & Thomas, D. P. Effect of exercise training on passive stiffness in locomotor skeletal muscle: role of extracellular matrix. J. Appl. Physiol. 85, 1011–1016 (1998).

    CAS  PubMed  Google Scholar 

  48. Haus, J. M., Carrithers, J. A., Trappe, S. W. & Trappe, T. A. Collagen, cross-linking, and advanced glycation end products in aging human skeletal muscle. J. Appl. Physiol. 103, 2068–2076 (2007).

    CAS  PubMed  Google Scholar 

  49. Hoelz, A., Debler, E. W. & Blobel, G. The structure of the nuclear pore complex. Annu. Rev. Biochem. 80, 613–643 (2011).

    CAS  PubMed  Google Scholar 

  50. Cronshaw, J. M., Krutchinsky, A. N., Zhang, W., Chait, B. T. & Matunis, M. J. Proteomic analysis of the mammalian nuclear pore complex. J. Cell Biol. 158, 915–927 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Hetzer, M. W. & Wente, S. R. Border control at the nucleus: biogenesis and organization of the nuclear membrane and pore complexes. Dev. Cell 17, 606–616 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Wente, S. R. & Rout, M. P. The nuclear pore complex and nuclear transport. Cold Spring Harb. Perspect. Biol. 2, a000562 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ribbeck, K. & Gorlich, D. Kinetic analysis of translocation through nuclear pore complexes. EMBO J. 20, 1320–1330 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Garcia-Segura, L. M., Lafarga, M., Berciano, M. T., Hernandez, P. & Andres, M. A. Distribution of nuclear pores and chromatin organization in neurons and glial cells of the rat cerebellar cortex. J. Comp. Neurol. 290, 440–450 (1989).

    CAS  PubMed  Google Scholar 

  55. Stavru, F. et al. NDC1: a crucial membrane-integral nucleoporin of metazoan nuclear pore complexes. J. Cell Biol. 173, 509–519 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hallberg, E., Wozniak, R. W. & Blobel, G. An integral membrane protein of the pore membrane domain of the nuclear envelope contains a nucleoporin-like region. J. Cell Biol. 122, 513–521 (1993).

    CAS  PubMed  Google Scholar 

  57. Greber, U. F., Senior, A. & Gerace, L. A major glycoprotein of the nuclear pore complex is a membrane-spanning polypeptide with a large lumenal domain and a small cytoplasmic tail. EMBO J. 9, 1495–1502 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Siniossoglou, S. et al. A novel complex of nucleoporins, which includes Sec13p and a Sec13p homolog, is essential for normal nuclear pores. Cell 84, 265–275 (1996).

    CAS  PubMed  Google Scholar 

  59. Grandi, P. et al. Nup93, a vertebrate homologue of yeast Nic96p, forms a complex with a novel 205 kDa protein and is required for correct nuclear pore assembly. Mol. Biol. Cell 8, 2017–2038 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Alber, F. et al. The molecular architecture of the nuclear pore complex. Nature 450, 695–701 (2007).

    CAS  PubMed  Google Scholar 

  61. Hu, T., Guan, T. & Gerace, L. Molecular and functional characterization of the p62 complex, an assembly of nuclear pore complex glycoproteins. J. Cell Biol. 134, 589–601 (1996).

    CAS  PubMed  Google Scholar 

  62. Frey, S., Richter, R. P. & Gorlich, D. FG-rich repeats of nuclear pore proteins form a three-dimensional meshwork with hydrogel-like properties. Science 314, 815–817 (2006).

    CAS  PubMed  Google Scholar 

  63. Hulsmann, B. B., Labokha, A. A. & Gorlich, D. The permeability of reconstituted nuclear pores provides direct evidence for the selective phase model. Cell 150, 738–751 (2012).

    PubMed  Google Scholar 

  64. Rabut, G., Doye, V. & Ellenberg, J. Mapping the dynamic organization of the nuclear pore complex inside single living cells. Nature Cell Biol. 6, 1114–1121 (2004).

    CAS  PubMed  Google Scholar 

  65. Woulfe, J. M. Abnormalities of the nucleus and nuclear inclusions in neurodegenerative disease: a work in progress. Neuropathol. Appl. Neurobiol. 33, 2–42 (2007).

    CAS  PubMed  Google Scholar 

  66. Lenart, P. et al. Nuclear envelope breakdown in starfish oocytes proceeds by partial NPC disassembly followed by a rapidly spreading fenestration of nuclear membranes. J. Cell Biol. 160, 1055–1068 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Burke, B. & Ellenberg, J. Remodelling the walls of the nucleus. Nature Rev. Mol. Cell Biol. 3, 487–497 (2002).

    CAS  Google Scholar 

  68. Anderson, D. J. & Hetzer, M. W. Shaping the endoplasmic reticulum into the nuclear envelope. J. Cell Sci. 121, 137–142 (2008).

    CAS  PubMed  Google Scholar 

  69. Doucet, C. M., Talamas, J. A. & Hetzer, M. W. Cell cycle-dependent differences in nuclear pore complex assembly in metazoa. Cell 141, 1030–1041 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Spalding, K. L., Bhardwaj, R. D., Buchholz, B. A., Druid, H. & Frisen, J. Retrospective birth dating of cells in humans. Cell 122, 133–143 (2005).

    CAS  PubMed  Google Scholar 

  71. Dure, L. & Waters, L. Long-lived messenger RNA: evidence from cotton seed germination. Science 147, 410–412 (1965).

    CAS  PubMed  Google Scholar 

  72. Ford, P. J., Mathieson, T. & Rosbash, M. Very long-lived messenger RNA in ovaries of Xenopus laevis. Dev. Biol. 57, 417–426 (1977).

    CAS  PubMed  Google Scholar 

  73. Davison, A. N., Morgan, R. S., Wajda, M. & Wright, G. P. Metabolism of myelin lipids: incorporation of [3-14C]serine in brain lipids of the developing rabbit and their persistence in the central nervous system. J. Neurochem. 4, 360–365 (1959).

    CAS  Google Scholar 

  74. Davison, A. N. & Wajda, M. Metabolism of myelin lipids: estimation and separation of brain lipids in the developing rabbit. J. Neurochem. 4, 353–359 (1959).

    CAS  PubMed  Google Scholar 

  75. Feser, J. & Tyler, J. Chromatin structure as a mediator of aging. FEBS Lett. 585, 2041–2048 (2011).

    CAS  PubMed  Google Scholar 

  76. Bergmann, O. et al. Evidence for cardiomyocyte renewal in humans. Science 324, 98–102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Commerford, S. L., Carsten, A. L. & Cronkite, E. P. Histone turnover within nonproliferating cells. Proc. Natl Acad. Sci. USA 79, 1163–1165 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Duerre, J. A. & Lee, C. T. In vivo methylation and turnover of rat brain histones. J. Neurochem. 23, 541–547 (1974).

    CAS  PubMed  Google Scholar 

  79. Park, S. K., Venable, J. D., Xu, T. & Yates, J. R. A quantitative analysis software tool for mass spectrometry-based proteomics. Nature Methods 5, 319–322 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Robinson, N. E. & Robinson, A. B. Deamidation of human proteins. Proc. Natl Acad. Sci. USA 98, 12409–12413 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Semba, R. D., Nicklett, E. J. & Ferrucci, L. Does accumulation of advanced glycation end products contribute to the aging phenotype? J. Gerontol. A Biol. Sci. Med. Sci. 65, 963–975 (2010).

    PubMed  Google Scholar 

  82. Schleicher, E. D., Wagner, E. & Nerlich, A. G. Increased accumulation of the glycoxidation product Nɛ-(carboxymethyl)lysine in human tissues in diabetes and aging. J. Clin. Invest. 99, 457–468 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Liang, J. N. & Pelletier, M. R. Destabilization of lens protein conformation by glutathione mixed disulfide. Exp. Eye Res. 47, 17–25 (1988).

    CAS  PubMed  Google Scholar 

  84. Spector, A. & Roy, D. Disulfide-linked high molecular weight protein associated with human cataract. Proc. Natl Acad. Sci. USA 75, 3244–3248 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Miesbauer, L. R. et al. Post-translational modifications of water-soluble human lens crystallins from young adults. J. Biol. Chem. 269, 12494–12502 (1994).

    CAS  PubMed  Google Scholar 

  86. Lund, A. L., Smith, J. B. & Smith, D. L. Modifications of the water-insoluble human lens α-crystallins. Exp. Eye Res. 63, 661–672 (1996).

    CAS  PubMed  Google Scholar 

  87. Morimoto, R. I. The heat shock response: systems biology of proteotoxic stress in aging and disease. Cold Spring Harb. Symp. Quant. Biol. 76, 91–99 (2011).

    CAS  PubMed  Google Scholar 

  88. Moller, I. M., Rogowska-Wrzesinska, A. & Rao, R. S. Protein carbonylation and metal-catalyzed protein oxidation in a cellular perspective. J. Proteom. 74, 2228–2242 (2011).

    CAS  Google Scholar 

Download references

Acknowledgements

The authors thank members of the Hetzer laboratory and E.Q. Toyama for helpful suggestions and critical reading of the manuscript. B.H.T is supported by the Hewitt Foundation; M.W.H by the Ellison Medical Foundation, by the US National Institutes of Health (NIH) (R01GM098749) and the National Cancer Institute (award number P30CA014195).

Author information

Authors and Affiliations

  1. Brandon H. Toyama and Martin W. Hetzer are at the Salk Institute for Biological Studies, Molecular and Cell Biology Laboratory, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.,

    Brandon H. Toyama & Martin W. Hetzer

Authors
  1. Brandon H. Toyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin W. Hetzer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin W. Hetzer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Martin W. Hetzer's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Toyama, B., Hetzer, M. Protein homeostasis: live long, won't prosper. Nat Rev Mol Cell Biol 14, 55–61 (2013). https://doi.org/10.1038/nrm3496

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3496

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing