Article | Published:

An evolutionarily conserved pathway controls proteasome homeostasis

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

Abstract

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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Acknowledgements

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.

Author information

Affiliations

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

    • Adrien Rousseau
    •  & Anne Bertolotti

Authors

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Contributions

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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https://doi.org/10.1038/nature18943

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