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Ubiquitin receptors play redundant roles in the proteasomal degradation of the p53 repressor MDM2

Sparks, A., Kelly, C. J. and Saville, M. K. (2022) Ubiquitin receptors play redundant roles in the proteasomal degradation of the p53 repressor MDM2. FEBS Letters, 596(21), pp. 2746-2767. (doi: 10.1002/1873-3468.14436) (PMID:35735670)

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Abstract

Much remains to be determined about the participation of ubiquitin receptors in proteasomal degradation and their potential as therapeutic targets. Suppression of the ubiquitin receptor S5A/PSMD4/hRpn10 alone stabilises p53/TP53 but not the key p53 repressor MDM2. Here, we observed S5A and the ubiquitin receptors ADRM1/PSMD16/hRpn13 and RAD23A and B functionally overlap in MDM2 degradation. We provide further evidence that degradation of only a subset of ubiquitinated proteins is sensitive to S5A knockdown because ubiquitin receptor redundancy is commonplace. p53 can be upregulated by S5A modulation while degradation of substrates with redundant receptors is maintained. Our observations and analysis of Cancer Dependency Map (DepMap) screens show S5A depletion/loss substantially reduces cancer cell line viability. This and selective S5A dependency of proteasomal substrates make S5A a target of interest for cancer therapy.

Item Type:Articles
Additional Information:This work was funded by the Wellcome Trust (grant no. 094208/Z/10/Z). MKS was supported by the European Research Council (grant no. 250170).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Kelly, Dr Christopher
Authors: Sparks, A., Kelly, C. J., and Saville, M. K.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:FEBS Letters
Publisher:Wiley
ISSN:0014-5793
ISSN (Online):1873-3468
Published Online:23 June 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in FEBS Letters 596(21): 2746-2767
Publisher Policy:Reproduced under a Creative Commons License
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