The ubiquitin proteasome system degrades the great majority of proteins in mammalian cells. Countless studies have described how ubiquitination promotes the selective degradation of different cell proteins. However, there is a small but growing literature that protein half-lives can also be regulated by post-translational modifications of the 26S proteasome. The present study reviews the ability of several kinases to alter proteasome function through subunit phosphorylation. For example, PKA (protein kinase A) and DYRK2 (dual-specificity tyrosine-regulated kinase 2) stimulate the proteasome's ability to degrade ubiquitinated proteins, peptides, and adenosine triphosphate, while one kinase, ASK1 (apoptosis signal-regulating kinase 1), inhibits proteasome function during apoptosis. Proteasome phosphorylation is likely to be important in regulating protein degradation because it occurs downstream from many hormones and neurotransmitters, in conditions that raise cyclic adenosine monophosphate or cyclic guanosine monophosphate levels, after calcium influx following synaptic depolarization, and during phases of the cell cycle. Beyond its physiological importance, pharmacological manipulation of proteasome phosphorylation has the potential to combat various diseases. Inhibitors of phosphodiesterases by activating PKA or PKG (protein kinase G) can stimulate proteasomal degradation of misfolded proteins that cause neurodegenerative or myocardial diseases and even reduce the associated pathology in mouse models. These observations are promising since in many proteotoxic diseases, aggregation-prone proteins impair proteasome function, and disrupt protein homeostasis. Conversely, preventing subunit phosphorylation by DYRK2 slows cell cycle progression and tumor growth. However, further research is essential to determine how phosphorylation of different subunits by these (or other) kinases alters the properties of this complex molecular machine and thus influence protein degradation rates.
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October 2017
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Cover Image
Cover Image
The 26S proteasome. Image kindly provided by Professor Joel Kowit from his work Degradation, a depiction in stained glass of the 26S proteasome (see http://joelkowit.com). In this issue of the Biochemical Journal, VerPlank and Goldberg describe how phosphorylation of the proteasome regulates protein breakdown by reviewing the ability of several kinases to alter proteasome function; see pages 3355–3371 for further details.
Review Article|
September 25 2017
Regulating protein breakdown through proteasome phosphorylation
Jordan J.S. VerPlank;
Jordan J.S. VerPlank
1Harvard Medical School, Boston, MA 02115, U.S.A.
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Alfred L. Goldberg
1Harvard Medical School, Boston, MA 02115, U.S.A.
Correspondence: Alfred Goldberg (alfred_goldberg@hms.harvard.edu)
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Publisher: Portland Press Ltd
Received:
June 22 2017
Revision Received:
August 28 2017
Accepted:
August 30 2017
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Biochem J (2017) 474 (19): 3355–3371.
Article history
Received:
June 22 2017
Revision Received:
August 28 2017
Accepted:
August 30 2017
Citation
Jordan J.S. VerPlank, Alfred L. Goldberg; Regulating protein breakdown through proteasome phosphorylation. Biochem J 1 October 2017; 474 (19): 3355–3371. doi: https://doi.org/10.1042/BCJ20160809
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