Mechanisms and regulation of substrate degradation by the 26S proteasome

Connor Arkinson; Ken C Dong; Christine L Gee; Andreas Martin

doi:10.1038/s41580-024-00778-0

Mechanisms and regulation of substrate degradation by the 26S proteasome

Nat Rev Mol Cell Biol. 2024 Oct 3. doi: 10.1038/s41580-024-00778-0. Online ahead of print.

Authors

Connor Arkinson^{1

2

3}, Ken C Dong³, Christine L Gee^{1

2

3}, Andreas Martin^{4

5

6}

Affiliations

¹ California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA, USA.
² Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA.
³ Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA.
⁴ California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA, USA. a.martin@berkeley.edu.
⁵ Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA, USA. a.martin@berkeley.edu.
⁶ Howard Hughes Medical Institute, University of California at Berkeley, Berkeley, CA, USA. a.martin@berkeley.edu.

PMID: 39362999
DOI: 10.1038/s41580-024-00778-0

Abstract

The 26S proteasome is involved in degrading and regulating the majority of proteins in eukaryotic cells, which requires a sophisticated balance of specificity and promiscuity. In this Review, we discuss the principles that underly substrate recognition and ATP-dependent degradation by the proteasome. We focus on recent insights into the mechanisms of conventional ubiquitin-dependent and ubiquitin-independent protein turnover, and discuss the plethora of modulators for proteasome function, including substrate-delivering cofactors, ubiquitin ligases and deubiquitinases that enable the targeting of a highly diverse substrate pool. Furthermore, we summarize recent progress in our understanding of substrate processing upstream of the 26S proteasome by the p97 protein unfoldase. The advances in our knowledge of proteasome structure, function and regulation also inform new strategies for specific inhibition or harnessing the degradation capabilities of the proteasome for the treatment of human diseases, for instance, by using proteolysis targeting chimera molecules or molecular glues.

Publication types

Review