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Regulation of proteasome assembly and activity in health and disease


The proteasome degrades most cellular proteins in a controlled and tightly regulated manner and thereby controls many processes, including cell cycle, transcription, signalling, trafficking and protein quality control. Proteasomal degradation is vital in all cells and organisms, and dysfunction or failure of proteasomal degradation is associated with diverse human diseases, including cancer and neurodegeneration. Target selection is an important and well-established way to control protein degradation. In addition, mounting evidence indicates that cells adjust proteasome-mediated degradation to their needs by regulating proteasome abundance through the coordinated expression of proteasome subunits and assembly chaperones. Central to the regulation of proteasome assembly is TOR complex 1 (TORC1), which is the master regulator of cell growth and stress. This Review discusses how proteasome assembly and the regulation of proteasomal degradation are integrated with cellular physiology, including the interplay between the proteasome and autophagy pathways. Understanding these mechanisms has potential implications for disease therapy, as the misregulation of proteasome function contributes to human diseases such as cancer and neurodegeneration.

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  1. 1.

    Schoenheimer, R. & Clarke, H. T. The Dynamic State of Body Constituents (Harvard Univ. Press, 1942).

  2. 2.

    Young, V. R., Steffee, W. P., Pencharz, P. B., Winterer, J. C. & Scrimshaw, N. S. Total human body protein synthesis in relation to protein requirements at various ages. Nature 253, 192–194 (1975). This paper shows that the bulk of amino acids required for protein synthesis is provided by the recycling of existing proteins.

  3. 3.

    Nakatogawa, H., Suzuki, K., Kamada, Y. & Ohsumi, Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol. 10, 458–467 (2009).

  4. 4.

    Kaushik, S. & Cuervo, A. M. The coming of age of chaperone-mediated autophagy. Nat. Rev. Mol. Cell Biol. 19, 365–381 (2018).

  5. 5.

    Onodera, J. & Ohsumi, Y. Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation. J. Biol. Chem. 280, 31582–31586 (2005).This paper demonstrates the importance of autophagy, under nutrient starvation, for the maintenance of amino acid levels and protein synthesis.

  6. 6.

    Ohsumi, Y. Historical landmarks of autophagy research. Cell Res. 24, 9–23 (2014).

  7. 7.

    Finley, D. Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu. Rev. Biochem. 78, 477–513 (2009).

  8. 8.

    Varshavsky, A. Regulated protein degradation. Trends Biochem. Sci. 30, 283–286 (2005).

  9. 9.

    Ciechanover, A. Intracellular protein degradation: from a vague idea thru the lysosome and the ubiquitin–proteasome system and onto human diseases and drug targeting. Biochim. Biophys. Acta 1824, 3–13 (2012).

  10. 10.

    Tanaka, K. The proteasome: overview of structure and functions. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 85, 12–36 (2009).

  11. 11.

    Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).

  12. 12.

    Suraweera, A., Münch, C., Hanssum, A. & Bertolotti, A. Failure of amino acid homeostasis causes cell death following proteasome inhibition. Mol. Cell 48, 242–253 (2012). This paper demonstrates that a vital function of the proteasome, under normal conditions, is to recycle amino acid levels.

  13. 13.

    Komander, D. & Rape, M. The ubiquitin code. Annu. Rev. Biochem. 81, 203–229 (2012).

  14. 14.

    Yu, H. & Matouschek, A. Recognition of client proteins by the proteasome. Annu. Rev. Biophys. 46, 149–173 (2017).

  15. 15.

    Saeki, Y. Ubiquitin recognition by the proteasome. J. Biochem. 161, 113–124 (2017).

  16. 16.

    Prakash, S., Tian, L., Ratliff, K. S., Lehotzky, R. E. & Matouschek, A. An unstructured initiation site is required for efficient proteasome-mediated degradation. Nat. Struct. Mol. Biol. 11, 830–837 (2004). This paper establishes the concept that an unstructured region is required to initiate protein degradation by the proteasome.

  17. 17.

    Inobe, T. & Matouschek, A. Paradigms of protein degradation by the proteasome. Curr. Opin. Struct. Biol. 24, 156–164 (2014).

  18. 18.

    Huang, X. & Dixit, V. M. Drugging the undruggables: exploring the ubiquitin system for drug development. Cell Res. 26, 484 (2016).

  19. 19.

    Schmidt, M. & Finley, D. Regulation of proteasome activity in health and disease. Biochim. Biophys. Acta 1843, 13–25 (2014).

  20. 20.

    Collins, G. A. & Goldberg, A. L. The logic of the 26S proteasome. Cell 169, 792–806 (2017).

  21. 21.

    Murata, S., Yashiroda, H. & Tanaka, K. Molecular mechanisms of proteasome assembly. Nat. Rev. Mol. Cell. Biol. 10, 104–115 (2009).

  22. 22.

    Lander, G. C. et al. Complete subunit architecture of the proteasome regulatory particle. Nature 482, 186–191 (2012). This paper provides the structure of the proteasome RP by cryo-electron microscopy.

  23. 23.

    Budenholzer, L., Cheng, C. L., Li, Y. & Hochstrasser, M. Proteasome structure and assembly. J. Mol. Biol. 429, 3500–3524 (2017).

  24. 24.

    Pick, E. & Berman, T. S. Formation of alternative proteasomes: same lady, different cap? FEBS Lett. 587, 389–393 (2013).

  25. 25.

    Stadtmueller, B. M. & Hill, C. P. Proteasome activators. Mol. Cell 41, 8–19 (2011).

  26. 26.

    Goldberg, A. L. Functions of the proteasome: from protein degradation and immune surveillance to cancer therapy. Biochem. Soc. Trans. 35, 12–17 (2007).

  27. 27.

    Cascio, P. PA28αβ: the enigmatic magic ring of the proteasome? Biomolecules 4, 566–584 (2014).

  28. 28.

    Huber, E. M. & Groll, M. The mammalian proteasome activator PA28 forms an asymmetric α4β3 complex. Structure 25, 1473–1480 (2017).

  29. 29.

    Coux, O., Tanaka, K. & Goldberg, A. L. Structure and functions of the 20S and 26S proteasomes. Annu. Rev. Biochem. 65, 801–847 (1996).

  30. 30.

    Lupas, A., Zwickl, P., Wenzel, T., Seemüller, E. & Baumeister, W. Structure and function of the 20S proteasome and of its regulatory complexes. Cold Spring Harb. Symp. Quant. Biol. 60, 515–524 (1995).

  31. 31.

    Kunjappu, M. J. & Hochstrasser, M. Assembly of the 20S proteasome. Biochim. Biophys. Acta 1843, 2–12 (2014).

  32. 32.

    Groll, M. et al. Structure of 20S proteasome from yeast at 2.4 Å resolution. Nature 386, 463–471 (1997).

  33. 33.

    Unno, M. et al. The structure of the mammalian 20S proteasome at 2.75 Å resolution. Structure 10, 609–618 (2002).

  34. 34.

    Arendt, C. S. & Hochstrasser, M. Identification of the yeast 20S proteasome catalytic centers and subunit interactions required for active-site formation. Proc. Natl Acad. Sci. USA 94, 7156–7161 (1997).

  35. 35.

    Griffin, T. A. et al. Immunoproteasome assembly: cooperative incorporation of interferon γ (IFN-γ)-inducible subunits. J. Exp. Med. 187, 97–104 (1998).

  36. 36.

    Heink, S., Ludwig, D., Kloetzel, P.-M. & Krüger, E. IFN-gamma-induced immune adaptation of the proteasome system is an accelerated and transient response. Proc. Natl Acad. Sci. USA 102, 9241–9246 (2005).

  37. 37.

    Florea, B. I. et al. Activity-based profiling reveals reactivity of the murine thymoproteasome-specific subunit beta5t. Chem. Biol. 17, 795–801 (2010).

  38. 38.

    Ripen, A. M., Nitta, T., Murata, S., Tanaka, K. & Takahama, Y. Ontogeny of thymic cortical epithelial cells expressing the thymoproteasome subunit β5t. Eur. J. Immunol. 41, 1278–1287 (2011).

  39. 39.

    Bhattacharyya, S., Yu, H., Mim, C. & Matouschek, A. Regulated protein turnover: snapshots of the proteasome in action. Nat. Rev. Mol. Cell. Biol. 15, 122–133 (2014).

  40. 40.

    Bedford, L., Paine, S., Sheppard, P. W., Mayer, R. J. & Roelofs, J. Assembly, structure and function of the 26S proteasome. Trends Cell Biol. 20, 391–401 (2010).

  41. 41.

    Tomko, R. J. & Hochstrasser, M. Molecular architecture and assembly of the eukaryotic proteasome. Annu. Rev. Biochem. 82, 415–445 (2013).

  42. 42.

    Glickman, M. H. et al. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell 94, 615–623 (1998).

  43. 43.

    Dambacher, C. M., Worden, E. J., Herzik, M. A. Jr, Martin, A. & Lander, G. C. Atomic structure of the 26S proteasome lid reveals the mechanism of deubiquitinase inhibition. eLife 5, e13027 (2016).

  44. 44.

    Schweitzer, A. et al. Structure of the human 26S proteasome at a resolution of 3.9 Å. Proc. Natl Acad. Sci. USA 113, 7816–7821 (2016).

  45. 45.

    da Fonseca, P. C. A., He, J. & Morris, E. P. Molecular model of the human 26S proteasome. Mol. Cell 46, 54–66 (2012).

  46. 46.

    Witt, E. et al. Characterisation of the newly identified human Ump1 homologue POMP and analysis of LMP7(β5i) incorporation into 20S proteasomes. J. Mol. Biol. 301, 1–9 (2000).

  47. 47.

    Hirano, Y. et al. A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes. Nature 437, 1381–1385 (2005). This paper identifies two chaperones involved in the maturation of mammalian 20S proteasomes.

  48. 48.

    Hirano, Y. et al. Cooperation of multiple chaperones required for the assembly of mammalian 20S proteasomes. Mol. Cell 24, 977–984 (2006).

  49. 49.

    Le Tallec, B. et al. 20S proteasome assembly is orchestrated by two distinct pairs of chaperones in yeast and in mammals. Mol. Cell 27, 660–674 (2007).

  50. 50.

    Wani, P. S., Rowland, M. A., Ondracek, A., Deeds, E. J. & Roelofs, J. Maturation of the proteasome core particle induces an affinity switch that controls regulatory particle association. Nat. Commun. 6, 6384 (2015).

  51. 51.

    Stadtmueller, B. M. et al. Structure of a proteasome Pba1-Pba2 complex: implications for proteasome assembly, activation, and biological function. J. Biol. Chem. 287, 37371–37382 (2012).

  52. 52.

    Kusmierczyk, A. R. & Hochstrasser, M. Some assembly required: dedicated chaperones in eukaryotic proteasome biogenesis. Biol. Chem. 389, 1143–1151 (2008).

  53. 53.

    Kusmierczyk, A. R., Kunjappu, M. J., Funakoshi, M. & Hochstrasser, M. A multimeric assembly factor controls the formation of alternative 20S proteasomes. Nat. Struct. Mol. Biol. 15, 237–244 (2008).

  54. 54.

    Padmanabhan, A., Vuong, S. A.-T. & Hochstrasser, M. Assembly of an evolutionarily conserved alternative proteasome isoform in human cells. Cell Rep. 14, 2962–2974 (2016).

  55. 55.

    Hirano, Y. et al. Dissecting β-ring assembly pathway of the mammalian 20S proteasome. EMBO J. 27, 2204–2213 (2008).

  56. 56.

    Li, X., Kusmierczyk, A. R., Wong, P., Emili, A. & Hochstrasser, M. β-Subunit appendages promote 20S proteasome assembly by overcoming an Ump1-dependent checkpoint. EMBO J. 26, 2339–2349 (2007).

  57. 57.

    Li, X., Li, Y., Arendt, C. S. & Hochstrasser, M. Distinct elements in the proteasomal β5 subunit propeptide required for autocatalytic processing and proteasome assembly. J. Biol. Chem. 291, 1991–2003 (2016).

  58. 58.

    Ramos, P. C., Höckendorff, J., Johnson, E. S., Varshavsky, A. & Dohmen, R. J. Ump1p is required for proper maturation of the 20S proteasome and becomes its substrate upon completion of the assembly. Cell 92, 489–499 (1998).

  59. 59.

    Kock, M. et al. Proteasome assembly from 15S precursors involves major conformational changes and recycling of the Pba1–Pba2 chaperone. Nat. Commun. 6, 6123 (2015).

  60. 60.

    Tomko, R. J. Jr & Hochstrasser, M. Incorporation of the Rpn12 subunit couples completion of proteasome regulatory particle lid assembly to lid-base joining. Mol. Cell 44, 907–917 (2011).

  61. 61.

    Funakoshi, M., Tomko, R. J. Jr, Kobayashi, H. & Hochstrasser, M. Multiple assembly chaperones govern biogenesis of the proteasome regulatory particle base. Cell 137, 887–899 (2009).

  62. 62.

    Kaneko, T. et al. Assembly pathway of the mammalian proteasome base subcomplex is mediated by multiple specific chaperones. Cell 137, 914–925 (2009).

  63. 63.

    Saeki, Y. et al. Multiple proteasome-interacting proteins assist the assembly of the yeast 19S regulatory particle. Cell 137, 900–913 (2009).

  64. 64.

    Le Tallec, B., Barrault, M.-B., Guérois, R., Carré, T. & Peyroche, A. Hsm3/S5b participates in the assembly pathway of the 19S regulatory particle of the proteasome. Mol. Cell 33, 389–399 (2009).

  65. 65.

    Hanssum, A. et al. An inducible chaperone adapts proteasome assembly to stress. Mol. Cell 55, 566–577 (2014). This paper shows that proteasome assembly is regulated.

  66. 66.

    Roelofs, J. et al. Chaperone-mediated pathway of proteasome regulatory particle assembly. Nature 459, 861–865 (2009).

  67. 67.

    Park, S. et al. Reconfiguration of the proteasome during chaperone-mediated assembly. Nature 497, 512–516 (2013).

  68. 68.

    Park, S. et al. Hexameric assembly of the proteasomal ATPases is templated through their C termini. Nature 459, 866–870 (2009). Refs 61, 62, 63, 66 and 68 identify assembly chaperones for the RPs of the proteasome.

  69. 69.

    Tomko, R. J., Funakoshi, M., Schneider, K., Wang, J. & Hochstrasser, M. Heterohexameric ring arrangement of the eukaryotic proteasomal ATPases: implications for proteasome structure and assembly. Mol. Cell 38, 393–403 (2010).

  70. 70.

    Förster, F. et al. An atomic model AAA-ATPase/20S core particle sub-complex of the 26S proteasome. Biochem. Biophys. Res. Commun. 388, 228–233 (2009).

  71. 71.

    Li, F. et al. Nucleotide-dependent switch in proteasome assembly mediated by the Nas6 chaperone. Proc. Natl Acad. Sci. USA 114, 1548–1553 (2017).

  72. 72.

    Satoh, T. et al. Structural basis for proteasome formation controlled by an assembly chaperone Nas2. Structure 22, 731–743 (2014).

  73. 73.

    Barrault, M.-B. et al. Dual functions of the Hsm3 protein in chaperoning and scaffolding regulatory particle subunits during the proteasome assembly. Proc. Natl Acad. Sci. USA 109, E1001–E1010 (2012).

  74. 74.

    Tomko, Jr., R. J. & Hochstrasser, M. The intrinsically disordered Sem1 protein functions as a molecular tether during proteasome lid biogenesis. Mol. Cell 53, 433–443 (2014).

  75. 75.

    Fukunaga, K., Kudo, T., Toh-e, A., Tanaka, K. & Saeki, Y. Dissection of the assembly pathway of the proteasome lid in Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 396, 1048–1053 (2010).

  76. 76.

    Estrin, E., Lopez-Blanco, J. R., Chacón, P. & Martin, A. Formation of an Intricate helical bundle dictates the assembly of the 26S proteasome lid. Structure 21, 1624–1635 (2013).

  77. 77.

    Tomko, R. J. et al. A single α helix drives extensive remodeling of the proteasome lid and completion of regulatory particle assembly. Cell 163, 432–444 (2015).

  78. 78.

    Park, S., Tian, G., Roelofs, J. & Finley, D. Assembly manual for the proteasome regulatory particle: the first draft. Biochem. Soc. Trans. 38, 6–13 (2010).

  79. 79.

    Sokolova, V., Li, F., Polovin, G. & Park, S. Proteasome activation is mediated via a functional switch of the Rpt6 C-terminal tail following chaperone-dependent assembly. Sci. Rep. 5, 14909 (2015).

  80. 80.

    Shi, Y. et al. Rpn1 provides adjacent receptor sites for substrate binding and deubiquitination by the proteasome. Science 351, aad9421 (2016).

  81. 81.

    van Nocker, S. et al. The multiubiquitin-chain-binding protein Mcb1 is a component of the 26S proteasome in Saccharomyces cerevisiae and plays a nonessential, substrate-specific role in protein turnover. Mol. Cell. Biol. 16, 6020–6028 (1996).

  82. 82.

    Hamazaki, J., Hirayama, S. & Murata, S. Redundant roles of Rpn10 and Rpn13 in recognition of ubiquitinated proteins and cellular homeostasis. PLOS Genet. 11, e1005401 (2015).

  83. 83.

    Hamazaki, J. et al. Rpn10-mediated degradation of ubiquitinated proteins is essential for mouse development. Mol. Cell. Biol. 27, 6629–6638 (2007).

  84. 84.

    de Poot, S. A. H., Tian, G. & Finley, D. Meddling with fate: the proteasomal deubiquitinating enzymes. J. Mol. Biol. 429, 3525–3545 (2017).

  85. 85.

    Lee, B.-H. et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179–184 (2010).

  86. 86.

    Hoyt, M. A. & Coffino, P. Ubiquitin-free routes into the proteasome. Cell. Mol. Life Sci. 61, 1596–1600 (2004).

  87. 87.

    Ben-Nissan, G. & Sharon, M. Regulating the 20S proteasome ubiquitin-independent degradation pathway. Biomolecules 4, 862–884 (2014).

  88. 88.

    Navon, A. & Ciechanover, A. The 26S proteasome: from basic mechanisms to drug targeting. J. Biol. Chem. 284, 33713–33718 (2009).

  89. 89.

    Mannhaupt, G., Schnall, R., Karpov, V., Vetter, I. & Feldmann, H. Rpn4p acts as a transcription factor by binding to PACE, a nonamer box found upstream of 26S proteasomal and other genes in yeast. FEBS Lett. 450, 27–34 (1999).

  90. 90.

    Xie, Y. & Varshavsky, A. RPN4 is a ligand, substrate, and transcriptional regulator of the 26S proteasome: a negative feedback circuit. Proc. Natl Acad. Sci. USA 98, 3056–3061 (2001). This paper identifies a transcription factor that controls expression of all proteasome subunits.

  91. 91.

    Ma, M. & Liu, Z. L. Comparative transcriptome profiling analyses during the lag phase uncover YAP1, PDR1, PDR3, RPN4, and HSF1 as key regulatory genes in genomic adaptation to the lignocellulose derived inhibitor HMF for Saccharomyces cerevisiae. BMC Genomics 11, 660 (2010).

  92. 92.

    Meiners, S. et al. Inhibition of proteasome activity induces concerted expression of proteasome genes and de novo formation of mammalian proteasomes. J. Biol. Chem. 278, 21517–21525 (2003).

  93. 93.

    Kwak, M.-K., Wakabayashi, N., Greenlaw, J. L., Yamamoto, M. & Kensler, T. W. Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol. Cell. Biol. 23, 8786–8794 (2003).

  94. 94.

    Radhakrishnan, S. K. et al. Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells. Mol. Cell 38, 17–28 (2010).

  95. 95.

    Taguchi, K., Motohashi, H. & Yamamoto, M. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 16, 123–140 (2011).

  96. 96.

    Kraft, D. C., Deocaris, C. C., Wadhwa, R. & Rattan, S. I. S. Preincubation with the proteasome inhibitor MG-132 enhances proteasome activity via the Nrf2 transcription factor in aging human skin fibroblasts. Ann. NY Acad. Sci. 1067, 420–424 (2006).

  97. 97.

    Koizumi, S. et al. The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction. eLife 5, e18357 (2016).

  98. 98.

    Lehrbach, N. J. & Ruvkun, G. Proteasome dysfunction triggers activation of SKN-1A/Nrf1 by the aspartic protease DDI-1. eLife 5, e17721 (2016).

  99. 99.

    Sykiotis, G. P. & Bohmann, D. Stress-activated cap’n’collar transcription factors in aging and human disease. Sci. Signal. 3, re3 (2010).

  100. 100.

    Kwak, M.-K. et al. Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J. Biol. Chem. 278, 8135–8145 (2003).

  101. 101.

    Kapeta, S., Chondrogianni, N. & Gonos, E. S. Nuclear erythroid factor 2-mediated proteasome activation delays senescence in human fibroblasts. J. Biol. Chem. 285, 8171–8184 (2010).

  102. 102.

    Sha, Z. & Goldberg, A. L. Proteasome-mediated processing of Nrf1 is essential for coordinate induction of all proteasome subunits and p97. Curr. Biol. 24, 1573–1583 (2014).

  103. 103.

    Gladman, N. P., Marshall, R. S., Lee, K.-H. & Vierstra, R. D. The proteasome stress regulon is controlled by a pair of NAC transcription factors in Arabidopsis. Plant Cell 28, 1279–1296 (2016).

  104. 104.

    Yabuta, Y. et al. Identification of recognition sequence of ANAC078 protein by the cyclic amplification and selection of targets technique. Plant Signal. Behav. 5, 695–697 (2010).

  105. 105.

    Nguyen, H. M. et al. An upstream regulator of the 26S proteasome modulates organ size in Arabidopsis thaliana. Plant J. 74, 25–36 (2013).

  106. 106.

    Rousseau, A. & Bertolotti, A. An evolutionarily conserved pathway controls proteasome homeostasis. Nature 536, 184–189 (2016). This paper identifies a signalling pathway controlling proteasome assembly.

  107. 107.

    Gao, X. et al. Quantitative profiling of initiating ribosomes in vivo. Nat. Methods 12, 147–153 (2015).

  108. 108.

    Shirozu, R., Yashiroda, H. & Murata, S. Identification of minimum Rpn4-responsive elements in genes related to proteasome functions. FEBS Lett. 589, 933–940 (2015).

  109. 109.

    Zhang, X. et al. MicroRNA-101 suppresses tumor cell proliferation by acting as an endogenous proteasome inhibitor via targeting the proteasome assembly factor POMP. Mol. Cell 59, 243–257 (2015).

  110. 110.

    Wrobel, L. et al. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524, 485–488 (2015).

  111. 111.

    Lee, W. et al. iRhom1 regulates proteasome activity via PAC1/2 under ER stress. Sci. Rep. 5, 11559 (2015).

  112. 112.

    Freeman, M. The Rhomboid-like superfamily: molecular mechanisms and biological roles. Annu. Rev. Cell Dev. Biol. 30, 235–254 (2014).

  113. 113.

    Zettl, M., Adrain, C., Strisovsky, K., Lastun, V. & Freeman, M. Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling. Cell 145, 79–91 (2011).

  114. 114.

    Bergbold, N. & Lemberg, M. K. Emerging role of rhomboid family proteins in mammalian biology and disease. Biochim. Biophys. Acta 1828, 2840–2848 (2013).

  115. 115.

    Akahane, T., Sahara, K., Yashiroda, H., Tanaka, K. & Murata, S. Involvement of Bag6 and the TRC pathway in proteasome assembly. Nat. Commun. 4, 3234 (2013).

  116. 116.

    Smith, D. M. et al. Docking of the proteasomal ATPases’ carboxyl termini in the 20S proteasome’s alpha ring opens the gate for substrate entry. Mol. Cell 27, 731–744 (2007).

  117. 117.

    Šledž, P. et al. Structure of the 26S proteasome with ATP-γS bound provides insights into the mechanism of nucleotide-dependent substrate translocation. Proc. Natl Acad. Sci. USA 110, 7264–7269 (2013).

  118. 118.

    Bajorek, M., Finley, D. & Glickman, M. H. Proteasome disassembly and downregulation is correlated with viability during stationary phase. Curr. Biol. 13, 1140–1144 (2003).

  119. 119.

    Kleijnen, M. F. et al. Stability of the proteasome can be regulated allosterically through engagement of its proteolytic active sites. Nat. Struct. Mol. Biol. 14, 1180–1188 (2007).

  120. 120.

    Wang, X., Yen, J., Kaiser, P. & Huang, L. Regulation of the 26S proteasome complex during oxidative stress. Sci. Signal. 3, ra88 (2010).

  121. 121.

    Liu, C.-W. et al. ATP binding and ATP hydrolysis play distinct roles in the function of 26S proteasome. Mol. Cell 24, 39–50 (2006).

  122. 122.

    Livnat-Levanon, N. et al. Reversible 26S proteasome disassembly upon mitochondrial stress. Cell Rep. 7, 1371–1380 (2014).

  123. 123.

    Imai, J., Maruya, M., Yashiroda, H., Yahara, I. & Tanaka, K. The molecular chaperone Hsp90 plays a role in the assembly and maintenance of the 26S proteasome. EMBO J. 22, 3557–3567 (2003).

  124. 124.

    Yamano, T. et al. Hsp90-mediated assembly of the 26S proteasome is involved in major histocompatibility complex class I antigen processing. J. Biol. Chem. 283, 28060–28065 (2008).

  125. 125.

    Acquah, J.-R. Q., Haratake, K., Rakwal, R., Udono, H. & Chiba, T. Hsp90 and ECM29 are important to maintain the integrity of mammalian 26S proteasome. Adv. Biol. Chem. 05, 255 (2015).

  126. 126.

    Schopf, F. H., Biebl, M. M. & Buchner, J. The HSP90 chaperone machinery. Nat. Rev. Mol. Cell. Biol. 18, 345–360 (2017).

  127. 127.

    Vilchez, D. et al. RPN-6 determines C. elegans longevity under proteotoxic stress conditions. Nature 489, 263–268 (2012).

  128. 128.

    Vilchez, D. et al. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature 489, 304–308 (2012).

  129. 129.

    Lehmann, A., Niewienda, A., Jechow, K., Janek, K. & Enenkel, C. Ecm29 fulfils quality control functions in proteasome assembly. Mol. Cell 38, 879–888 (2010).

  130. 130.

    Park, S., Kim, W., Tian, G., Gygi, S. P. & Finley, D. Structural defects in the regulatory particle-core particle interface of the proteasome induce a novel proteasome stress response. J. Biol. Chem. 286, 36652–36666 (2011).

  131. 131.

    De La Mota-Peynado, A. et al. The proteasome-associated protein Ecm29 inhibits proteasomal ATPase activity and in vivo protein degradation by the proteasome. J. Biol. Chem. 288, 29467–29481 (2013).

  132. 132.

    Lee, S. Y.-C., De La Mota-Peynado, A. & Roelofs, J. Loss of Rpt5 protein interactions with the core particle and Nas2 protein causes the formation of faulty proteasomes that are inhibited by Ecm29 protein. J. Biol. Chem. 286, 36641–36651 (2011).

  133. 133.

    Wang, X. et al. The proteasome-interacting Ecm29 protein disassembles the 26S proteasome in response to oxidative stress. J. Biol. Chem. 292, 16310–16320 (2017).

  134. 134.

    Asher, G., Reuven, N. & Shaul, Y. 20S proteasomes and protein degradation ‘by default’. BioEssays 28, 844–849 (2006).

  135. 135.

    Im, E. & Chung, K. C. Precise assembly and regulation of 26S proteasome and correlation between proteasome dysfunction and neurodegenerative diseases. BMB Rep. 49, 459–473 (2016).

  136. 136.

    Livneh, I., Cohen-Kaplan, V., Cohen-Rosenzweig, C., Avni, N. & Ciechanover, A. The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death. Cell Res. 26, 869 (2016).

  137. 137.

    Guo, X., Huang, X. & Chen, M. J. Reversible phosphorylation of the 26S proteasome. Protein Cell 8, 255–272 (2017).

  138. 138.

    Satoh, K., Sasajima, H., Nyoumura, K., Yokosawa, H. & Sawada, H. Assembly of the 26S proteasome is regulated by phosphorylation of the p45/Rpt6 ATPase subunit. Biochemistry 40, 314–319 (2001).

  139. 139.

    Pereira, M. E. & Wilk, S. Phosphorylation of the multicatalytic proteinase complex from bovine pituitaries by a copurifying cAMP-dependent protein kinase. Arch. Biochem. Biophys. 283, 68–74 (1990).

  140. 140.

    Lin, J.-T. et al. Regulation of feedback between protein kinase A and the proteasome system worsens Huntington’s disease. Mol. Cell. Biol. 33, 1073–1084 (2013).

  141. 141.

    Asai, M. et al. PKA rapidly enhances proteasome assembly and activity in in vivo canine hearts. J. Mol. Cell. Cardiol. 46, 452–462 (2009).

  142. 142.

    Myeku, N. et al. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat. Med. 22, 46–53 (2016).

  143. 143.

    Myeku, N., Wang, H. & Figueiredo-Pereira, M. E. cAMP stimulates the ubiquitin/proteasome pathway in rat spinal cord neurons. Neurosci. Lett. 527, 126–131 (2012).

  144. 144.

    Lokireddy, S., Kukushkin, N. V. & Goldberg, A. L. cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins. Proc. Natl Acad. Sci. USA 112, E7176–E7185 (2015).

  145. 145.

    Guo, X. et al. UBLCP1 is a 26S proteasome phosphatase that regulates nuclear proteasome activity. Proc. Natl Acad. Sci. USA 108, 18649–18654 (2011).

  146. 146.

    Sun, S. et al. Phosphatase UBLCP1 controls proteasome assembly. Open Biol. 7, 170042 (2017).

  147. 147.

    Cho-Park, P. F. & Steller, H. Proteasome regulation by ADP-ribosylation. Cell 153, 614–627 (2013).

  148. 148.

    Li, X., Thompson, D., Kumar, B. & DeMartino, G. N. Molecular and cellular roles of PI31 (PSMF1) protein in regulation of proteasome function. J. Biol. Chem. 289, 17392–17405 (2014).

  149. 149.

    Kikuchi, J. et al. Co and post-translational modifications of the 26S proteasome in yeast. Proteomics 10, 2769–2779 (2010).

  150. 150.

    Tanaka, K. & Matsuda, N. Proteostasis and neurodegeneration: the roles of proteasomal degradation and autophagy. Biochim. Biophys. Acta 1843, 197–204 (2014).

  151. 151.

    Dikic, I. Proteasomal and autophagic degradation systems. Annu. Rev. Biochem. 86, 193–224 (2017).

  152. 152.

    Pilla, E., Schneider, K. & Bertolotti, A. Coping with protein quality control failure. Annu. Rev. Cell Dev. Biol. 33, 439–465 (2017).

  153. 153.

    Marshall, R. S., Li, F., Gemperline, D. C., Book, A. J. & Vierstra, R. D. Autophagic degradation of the 26S proteasome is mediated by the dual ATG8/ubiquitin receptor RPN10 in Arabidopsis. Mol. Cell 58, 1053–1066 (2015).

  154. 154.

    Waite, K. A., De-La Mota-Peynado, A., Vontz, G. & Roelofs, J. Starvation induces proteasome autophagy with different pathways for core and regulatory particles. J. Biol. Chem. 291, 3239–3253 (2016).

  155. 155.

    Marshall, R. S., McLoughlin, F. & Vierstra, R. D. Autophagic turnover of inactive 26S proteasomes in yeast is directed by the ubiquitin receptor Cue5 and the Hsp42 chaperone. Cell Rep. 16, 1717–1732 (2016).

  156. 156.

    Cohen-Kaplan, V. et al. p62- and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome. Proc. Natl Acad. Sci. USA 113, E7490–E7499 (2016).

  157. 157.

    Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

  158. 158.

    González, A. & Hall, M. N. Nutrient sensing and TOR signaling in yeast and mammals. EMBO J. 36, 397–408 (2017).

  159. 159.

    Kim, J., Kundu, M., Viollet, B. & Guan, K.-L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

  160. 160.

    Martina, J. A., Chen, Y., Gucek, M. & Puertollano, R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8, 903–914 (2012).

  161. 161.

    Roczniak-Ferguson, A. et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5, ra42 (2012).

  162. 162.

    Settembre, C. et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31, 1095–1108 (2012).

  163. 163.

    Kaur, J. & Debnath, J. Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell. Biol. 16, 461–472 (2015).

  164. 164.

    Luo, T. et al. PSMD10/gankyrin induces autophagy to promote tumor progression through cytoplasmic interaction with ATG7 and nuclear transactivation of ATG7 expression. Autophagy 12, 1355–1371 (2016).

  165. 165.

    Zhang, Y. et al. Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 513, 440–443 (2014).

  166. 166.

    Zhao, J., Zhai, B., Gygi, S. P. & Goldberg, A. L. mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proc. Natl Acad. Sci. USA 112, 15790–15797 (2015).

  167. 167.

    Zhao, J. & Goldberg, A. L. Coordinate regulation of autophagy and the ubiquitin proteasome system by MTOR. Autophagy 12, 1967–1970 (2016).

  168. 168.

    Vabulas, R. M. & Hartl, F. U. Protein synthesis upon acute nutrient restriction relies on proteasome function. Science 310, 1960–1963 (2005). This paper demonstrates the importance of the proteasome, under nutrient starvation, for the maintenance of amino acid levels and protein synthesis.

  169. 169.

    Fujiwara, T. et al. Proteasomes are essential for yeast proliferation. cDNA cloning and gene disruption of two major subunits. J. Biol. Chem. 265, 16604–16613 (1990).

  170. 170.

    Gomes, A. V. Genetics of proteasome diseases. Scientifica (2013).

  171. 171.

    Parzych, K. et al. Inadequate fine-tuning of protein synthesis and failure of amino acid homeostasis following inhibition of the ATPase VCP/p97. Cell Death Dis. 6, e2031 (2015).

  172. 172.

    Chondrogianni, N., Sakellari, M., Lefaki, M., Papaevgeniou, N. & Gonos, E. S. Proteasome activation delays aging in vitro and in vivo. Free Radic. Biol. Med. 71, 303–320 (2014).

  173. 173.

    Saez, I. & Vilchez, D. The mechanistic links between proteasome activity, aging and age-related diseases. Curr. Genom. 15, 38–51 (2014).

  174. 174.

    Chondrogianni., N. et al. Proteasome activation: an innovative promising approach for delaying aging and retarding age-related diseases. Ageing Res. Rev. 23, 37–55 (2015).

  175. 175.

    Vilchez, D., Saez, I. & Dillin, A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat. Commun. 5, 6659 (2014).

  176. 176.

    Bertolotti, A. in Protein Chaperones and Protection from Neurodegenerative Diseases (ed. Witt, S. N.) 179–210 (Wiley-Blackwell, 2011).

  177. 177.

    Marshall, A. G. et al. Genetic background alters the severity and onset of neuromuscular disease caused by the loss of ubiquitin-specific protease 14 (Usp14). PLOS ONE 8, e84042 (2013).

  178. 178.

    López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

  179. 179.

    Finkel, T., Serrano, M. & Blasco, M. A. The common biology of cancer and ageing. Nature 448, 767–774 (2007).

  180. 180.

    Manasanch, E. E. & Orlowski, R. Z. Proteasome inhibitors in cancer therapy. Nat. Rev. Clin. Oncol. 14, 417–433 (2017).

  181. 181.

    Grigoreva, T. A., Tribulovich, V. G., Garabadzhiu, A. V., Melino, G. & Barlev, N. A. The 26S proteasome is a multifaceted target for anti-cancer therapies. Oncotarget 6, 24733–24749 (2015).

  182. 182.

    Acosta-Alvear, D. et al. Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits. eLife 4, e08153 (2015).

  183. 183.

    Langlands, F. E. et al. PSMD9 expression predicts radiotherapy response in breast cancer. Mol. Cancer 13, 73 (2014).

  184. 184.

    Hopper, J. L., Begum, N., Smith, L. & Hughes, T. A. The role of PSMD9 in human disease: future clinical and therapeutic implications. AIMS Mol. Sci. 2, 476–484 (2015).

  185. 185.

    Dawson, S., Higashitsuji, H., Wilkinson, A. J., Fujita, J. & Mayer, R. J. Gankyrin: a new oncoprotein and regulator of pRb and p53. Trends Cell Biol. 16, 229–233 (2006).

  186. 186.

    Higashitsuji, H. et al. The oncoprotein gankyrin binds to MDM2/HDM2, enhancing ubiquitylation and degradation of p53. Cancer Cell 8, 75–87 (2005).

  187. 187.

    Walerych, D. et al. Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat. Cell Biol. 18, 897–909 (2016).

  188. 188.

    Varambally, S. et al. Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 322, 1695–1699 (2008).

  189. 189.

    Li, B. et al. The nuclear factor (erythroid-derived 2)-like 2 and proteasome maturation protein axis mediates bortezomib resistance in multiple myeloma. J. Biol. Chem. 290, 29854–29868 (2015).

  190. 190.

    Hashimoto, J. et al. Novel in vitro protein fragment complementation assay applicable to high-throughput screening in a 1536-well format. J. Biomol. Screen. 14, 970–979 (2009).

  191. 191.

    Izumikawa, M. et al. JBIR-22, an inhibitor for protein-protein interaction of the homodimer of proteasome assembly factor 3. J. Nat. Prod. 73, 628–631 (2010).

  192. 192.

    Glynne, R. et al. A proteasome-related gene between the two ABC transporter loci in the class II region of the human MHC. Nature 353, 357 (1991).

  193. 193.

    Kelly, A. et al. Second proteasome-related gene in the human MHC class II region. Nature 353, 667 (1991).

  194. 194.

    Hisamatsu, H. et al. Newly identified pair of proteasomal subunits regulated reciprocally by interferon gamma. J. Exp. Med. 183, 1807–1816 (1996).

  195. 195.

    Nandi, D., Jiang, H. & Monaco, J. J. Identification of MECL-1 (LMP-10) as the third IFN-gamma-inducible proteasome subunit. J. Immunol. 156, 2361–2364 (1996).

  196. 196.

    Ortiz-Navarrete, V. et al. Subunit of the ‘20S’ proteasome (multicatalytic proteinase) encoded by the major histocompatibility complex. Nature 353, 662–664 (1991).

  197. 197.

    Groettrup, M. et al. A third interferon-γ-induced subunit exchange in the 20S proteasome. Eur. J. Immunol. 26, 863–869 (1996).

  198. 198.

    Eskandari, S. K., Seelen, M. A. J., Lin, G. & Azzi, J. R. The immunoproteasome: an old player with a novel and emerging role in alloimmunity. Am. J. Transplant. 17, 3033–3039 (2017).

  199. 199.

    Kaur, G. & Batra, S. Emerging role of immunoproteasomes in pathophysiology. Immunol. Cell Biol. 94, 812–820 (2016).

  200. 200.

    Kimura, H., Caturegli, P., Takahashi, M. & Suzuki, K. New Insights into the function of the immunoproteasome in immune and nonimmune cells. J. Immunol. Res. 2015, 541984 (2015).

  201. 201.

    Murata, S. et al. Regulation of CD8+ T cell development by thymus-specific proteasomes. Science 316, 1349–1353 (2007).

  202. 202.

    Tomaru, U. & Kasahara, M. Thymoproteasome: role in thymic selection and clinical significance as a diagnostic marker for thymic epithelial tumors. Arch. Immunol. Ther. Exp. 61, 357–365 (2013).

  203. 203.

    Kniepert, A. & Groettrup, M. The unique functions of tissue-specific proteasomes. Trends Biochem. Sci. 39, 17–24 (2014).

  204. 204.

    Qian, M.-X. et al. Acetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis. Cell 153, 1012–1024 (2013).

  205. 205.

    Uechi, H., Hamazaki, J. & Murata, S. Characterization of the testis-specific proteasome subunit α4s in mammals. J. Biol. Chem. 289, 12365–12374 (2014).

  206. 206.

    Reinke, A. et al. TOR complex 1 includes a novel component, Tco89p (YPL180w), and cooperates with Ssd1p to maintain cellular integrity in Saccharomyces cerevisiae. J. Biol. Chem. 279, 14752–14762 (2004).

  207. 207.

    Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002). This paper identifies TORC1, the complex sensitive to rapamycin.

  208. 208.

    Kim, D.-H. et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 11, 895–904 (2003).

  209. 209.

    Kim, D.-H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002). This paper sheds light on the nutrient-sensing complex signalling to TORC1.

  210. 210.

    Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189 (2002). This paper sheds light on the nutrient-sensing proteins upstream of TORC1.

  211. 211.

    Wang, L., Harris, T. E., Roth, R. A. & Lawrence, J. C. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J. Biol. Chem. 282, 20036–20044 (2007).

  212. 212.

    Sancak, Y. et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903–915 (2007).

  213. 213.

    Vander Haar, E., Lee, S.-I., Bandhakavi, S., Griffin, T. J. & Kim, D.-H. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat. Cell Biol. 9, 316–323 (2007).

  214. 214.

    Chantranupong, L. et al. The sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 9, 1–8 (2014).

  215. 215.

    Parmigiani, A. et al. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 9, 1281–1291 (2014).

  216. 216.

    Chantranupong, L. et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165, 153–164 (2016).

  217. 217.

    Saxton, R. A., Chantranupong, L., Knockenhauer, K. E., Schwartz, T. U. & Sabatini, D. M. Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature 536, 229–233 (2016).

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The authors’ laboratory is supported by the Medical Research Council (UK) MC_U105185860. A.B. is an honorary fellow of the University of Cambridge Clinical Neurosciences Department. A.R. was supported by a European Molecular Biology Organization (EMBO) long-term fellowship and an EMBO advanced fellowship.

Reviewer information

Nature Reviews Molecular Cell Biology thanks A. Matouschek and the other anonymous reviewers for their contribution to the peer review of this work.

Author information

A.R. and A.B. researched data for the article and wrote and revised the article.

Competing interests

The authors declare no competing interests.

Correspondence to Anne Bertolotti.

Supplementary information

  1. Supplementary table 1



A form of autophagy that entraps cytosolic components in small vesicles formed by invagination of the lysosomal membrane, either in bulk or selectively.

Chaperone-mediated autophagy

A form of selective autophagy involving the transfer of cytosolic components directly across the lysosomal membrane.


Tunicamycin blocks N-linked glycosylation, a post-translational modification required for the folding of many proteins in the endoplasmic reticulum (ER). Consequently, tunicamycin causes accumulation of misfolded proteins in the ER, a treatment used to induce ER stress.

Rhomboid-like family of proteases

A family of pseudoproteases (proteolytically inactive) that bind membrane proteins to regulate their fate.

Integrated stress response

Stress response signalling pathway that is controlled by four kinases, GCN2, PKR, PERK and HRI, that phosphorylate eIF2α in response to diverse cellular stresses.


An AAA+-ATPase involved in a variety of cellular processes through its ability to pull proteins out of membranes or protein complexes for proteasome degradation.

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Fig. 1: The ubiquitin–proteasome system.
Fig. 2: Models of 20S core particle assembly.
Fig. 3: Models of 19S regulatory particle assembly.
Fig. 4: Transcriptional regulation of proteasome subunits.
Fig. 5: Regulation of proteasome assembly.
Fig. 6: TORC1 integrates protein and amino acid homeostasis.