Review Article | Published:

Regulation of proteasome assembly and activity in health and disease

Abstract

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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Acknowledgements

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

Glossary

Microautophagy

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

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.

p97

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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Further reading

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.