Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis

Abstract

BACKGROUND: The 26S proteasome is at the heart of the ubiquitin-proteasome system, which is the key cellular pathway for the regulated degradation of proteins and enforcement of protein quality control. The 26S proteasome is an unusually large and complicated protease comprising a 28-subunit core particle (CP) capped by one or two 19-subunit regulatory particles (RP). Multiple activities within the RP process incoming ubiquitinated substrates for eventual degradation by the barrel-shaped CP. The large size and elaborate architecture of the proteasome have made it an exceptional model for understanding mechanistic themes in macromolecular assembly.

OBJECTIVE: In the present work, we highlight the most recent mechanistic insights into proteasome assembly, with particular emphasis on intrinsic and extrinsic factors regulating proteasome biogenesis. We also describe new and exciting questions arising about how proteasome assembly is regulated and deregulated in normal and diseased cells.

METHODS: A comprehensive literature search using the PubMed search engine was performed, and key findings yielding mechanistic insight into proteasome assembly were included in this review.

RESULTS: Key recent studies have revealed that proteasome biogenesis is dependent upon intrinsic features of the subunits themselves as well as extrinsic factors, many of which function as dedicated chaperones.

CONCLUSION: Cells rely on a diverse set of mechanistic strategies to ensure the rapid, efficient, and faithful assembly of proteasomes from their cognate subunits. Importantly, physiological as well as pathological changes to proteasome assembly are emerging as exciting paradigms to alter protein degradation in vivo.

Keywords

proteasome assembly / assembly chaperones / ubiquitin-proteasome system / proteolysis / macromolecular complex

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Acknowledgements

The authors apologize to their colleagues whose work could not be discussed due to space limitations. This work was supported in part by start-up funds from the Florida State University College of Medicine (R.J.T.Jr.) and by a Research Support Funds Grant from Indiana University-Purdue University Indianapolis (A.R.K.).

Compliance with ethics guidelines

Lauren A. Howell, Robert J. Tomko Jr. and Andrew R. Kusmierczyk declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

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