The deubiquitylase USP9X controls ribosomal stalling

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Clancy, Anne, Heride, Claire, Pinto-Fernández, Adán, Kallinos, Andreas ORCID: 0000-0001-8771-963X, Kayser-Bricker, Katherine J, Wang, Weiping, Smith, Victoria, Elcocks, Hannah, Davis, Simon, Fessler, Shawn et al (show 16 more authors) , McKinnon, Crystal, Katz, Marie, Hammonds, Tim, Jones, Neil P, O’Connell, Jonathan, Follows, Bruce, Mischke, Steven, Caravella, Justin A, Ioannidis, Stephanos, Dinsmore, Christopher, Kim, Sunkyu, Behrens, Axel ORCID: 0000-0002-1557-1143, Komander, David ORCID: 0000-0002-8092-4320, Kessler, Benedikt M ORCID: 0000-0002-8160-2446, Urbé, Sylvie and Clague, Michael J ORCID: 0000-0003-3355-9479 (2020) The deubiquitylase USP9X controls ribosomal stalling. [Internet Publication]

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Abstract

<jats:title>Abstract</jats:title><jats:p>When a ribosome stalls during translation, it runs the risk of collision with a trailing ribosome. Such an encounter leads to the formation of a stable di-ribosome complex, which needs to be resolved by a dedicated machinery. The initial stalling and the subsequent resolution of di-ribosomal complexes requires activity of Makorin and ZNF598 ubiquitin E3 ligases respectively, through ubiquitylation of the eS10 and uS10 sub-units of the ribosome. It is common for the stability of RING E3 ligases to be regulated by an interacting deubiquitylase (DUB), which often opposes auto-ubiquitylation of the E3. Here, we show that the DUB USP9X directly interacts with ZNF598 and regulates its abundance through the control of protein stability in human cells. We have developed a highly specific small molecule inhibitor of USP9X. Proteomics analysis, following inhibitor treatment of HCT116 cells, confirms previous reports linking USP9X with centrosome associated protein stability and reveals loss of ZNF598 and Makorin 2. In the absence of USP9X or following chemical inhibition of its catalytic activity, steady state levels of Makorins and ZNF598 are diminished and the ribosomal quality control pathway is impaired.</jats:p>

Item Type:	Internet Publication
Uncontrolled Keywords:	1.1 Normal biological development and functioning, 1 Underpinning research, Generic health relevance
Depositing User:	Symplectic Admin
Date Deposited:	24 Apr 2020 14:01
Last Modified:	20 Apr 2024 04:14
DOI:	10.1101/2020.04.15.042291
Open Access URL:	https://www.biorxiv.org/content/10.1101/2020.04.15...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3083531