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An evolutionarily conserved pathway controls proteasome homeostasis

Nature volume 536, pages 184189 (11 August 2016) | Download Citation


The proteasome is essential for the selective degradation of most cellular proteins, but how cells maintain adequate amounts of proteasome is unclear. Here we show that there is an evolutionarily conserved signalling pathway controlling proteasome homeostasis. Central to this pathway is TORC1, the inhibition of which induced all known yeast 19S regulatory particle assembly-chaperones (RACs), as well as proteasome subunits. Downstream of TORC1 inhibition, the yeast mitogen-activated protein kinase, Mpk1, acts to increase the supply of RACs and proteasome subunits under challenging conditions in order to maintain proteasomal degradation and cell viability. This adaptive pathway was evolutionarily conserved, with mTOR and ERK5 controlling the levels of the four mammalian RACs and proteasome abundance. Thus, the central growth and stress controllers, TORC1 and Mpk1/ERK5, endow cells with a rapid and vital adaptive response to adjust proteasome abundance in response to the rising needs of cells. Enhancing this pathway may be a useful therapeutic approach for diseases resulting from impaired proteasomal degradation.

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  1. 1.

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

  2. 2.

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

  3. 3.

    , & The proteasome: molecular machinery and pathophysiological roles. Biol. Chem. 393, 217–234 (2012)

  4. 4.

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

  5. 5.

    , , , & Hsm3/S5b participates in the assembly pathway of the 19S regulatory particle of the proteasome. Mol. Cell 33, 389–399 (2009)

  6. 6.

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

  7. 7.

    , , & Multiple assembly chaperones govern biogenesis of the proteasome regulatory particle base. Cell 137, 887–899 (2009)

  8. 8.

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

  9. 9.

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

  10. 10.

    et al. An inducible chaperone adapts proteasome assembly to stress. Mol. Cell 55, 566–577 (2014)

  11. 11.

    , & SnapShot: The unfolded protein response. Cell 140, 590–590.e2 (2010)

  12. 12.

    et al. A comprehensive genomic binding map of gene and chromatin regulatory proteins in Saccharomyces. Mol. Cell 41, 480–492 (2011)

  13. 13.

    et al. Sfp1 is a stress- and nutrient-sensitive regulator of ribosomal protein gene expression. Proc. Natl Acad. Sci. USA 101, 14315–14322 (2004)

  14. 14.

    et al. A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev. 18, 2491–2505 (2004)

  15. 15.

    et al. Sfp1 interaction with TORC1 and Mrs6 reveals feedback regulation on TOR signaling. Mol. Cell 33, 704–716 (2009)

  16. 16.

    & Transient sequestration of TORC1 into stress granules during heat stress. Mol. Cell 47, 242–252 (2012)

  17. 17.

    & SnapShot: mTOR signaling. Cell 129, 434.e1–434.e2 (2007)

  18. 18.

    & Target of rapamycin (TOR) in nutrient signaling and growth control. Genetics 189, 1177–1201 (2011)

  19. 19.

    , & mTOR: from growth signal integration to cancer, diabetes and ageing. Nature Rev. Mol. Cell Biol. 12, 21–35 (2011)

  20. 20.

    & Mitogen-activated protein kinase stimulation of Ca2+ signaling is required for survival of endoplasmic reticulum stress in yeast. Mol. Biol. Cell 14, 4296–4305 (2003)

  21. 21.

    & The protein kinase C pathway is required for viability in quiescence in Saccharomyces cerevisiae. Curr. Biol. 12, 588–593 (2002)

  22. 22.

    , , & Regulation of the cell integrity pathway by rapamycin-sensitive TOR function in budding yeast. J. Biol. Chem. 277, 43495–43504 (2002)

  23. 23.

    , , & A surveillance pathway monitors the fitness of the endoplasmic reticulum to control its inheritance. Cell 142, 256–269 (2010)

  24. 24.

    Regulation of cell wall biogenesis in Saccharomyces cerevisiae: the cell wall integrity signaling pathway. Genetics 189, 1145–1175 (2011)

  25. 25.

    et al. A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes. Nature 437, 1381–1385 (2005)

  26. 26.

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

  27. 27.

    & 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)

  28. 28.

    , , & Failure of amino acid homeostasis causes cell death following proteasome inhibition. Mol. Cell 48, 242–253 (2012)

  29. 29.

    , , & ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science 273, 1725–1728 (1996)

  30. 30.

    , , & A genomic screen identifies Dsk2p and Rad23p as essential components of ER-associated degradation. EMBO Rep. 5, 692–697 (2004)

  31. 31.

    et al. A molecular census of 26S proteasomes in intact neurons. Science 347, 439–442 (2015)

  32. 32.

    et al. Expressed in the yeast Saccharomyces cerevisiae, human ERK5 is a client of the Hsp90 chaperone that complements loss of the Slt2p (Mpk1p) cell integrity stress-activated protein kinase. Eukaryot. Cell 5, 1914–1924 (2006)

  33. 33.

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

  34. 34.

    , , & 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)

  35. 35.

    & mTOR signaling in cellular and organismal energetics. Curr. Opin. Cell Biol. 33, 55–66 (2015)

  36. 36.

    & Yeast transformation by the LiAc/SS carrier DNA/PEG method. Methods Mol. Biol. 313, 107–120 (2006)

  37. 37.

    et al. An improved method for whole protein extraction from yeast Saccharomyces cerevisiae. Yeast 28, 795–798 (2011)

  38. 38.

    Optimized protein extraction for quantitative proteomics of yeasts. PLoS One 2, e1078 (2007)

  39. 39.

    et al. Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol. Cell 26, 663–674 (2007)

  40. 40.

    , & Characterization of the proteasome using native gel electrophoresis. Methods Enzymol. 398, 353–363 (2005)

  41. 41.

    & Domains of Tra1 important for activator recruitment and transcription coactivator functions of SAGA and NuA4 complexes. Mol. Cell. Biol. 31, 818–831 (2011)

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We thank Y. Lee and M. Hochstrasser for the kind gift of Nas2, Nas6, Hsm3 and Rpn14 antibodies; D. H. Wolf for CPY*–HA and Δss-CPY*–GFP constructs; T. Maeda for the P-Sch9 antibody; and members of the Bertolotti laboratory for discussion. A.B. is an honorary fellow of the University of Cambridge Clinical Neurosciences Department. This work was supported by the Medical Research Council (UK) MC_U105185860. A.R. is supported by an EMBO long-term fellowship.

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  1. MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK

    • Adrien Rousseau
    •  & Anne Bertolotti


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A.R. designed, performed and analysed all experiments, prepared the figures and helped with the manuscript. A.B. designed and supervised the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Anne Bertolotti.

Reviewer Information Nature thanks S. Murata and D. Sabatini and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains Supplementary Tables 1-2, listing the strains and the plasmids used in the study, respectively, and Supplementary Figure 1 containing full-scan gel images with size indications corresponding to Figures 1a-e, 1g-h, 2c, 2e, 2g, 3a-b, 3e-g, 5a, 5c, 5e, 6a, 6c, 6e-f, 6h, and Extended Data Figures 1a, 2b, 2d, 3a-h, 5a-d, 6a-d, 6g-i, 7a, 7c, 7e, 7g, 7i, 7k, 8a, 8c, 9a, 9c and 10a.

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