TY - JOUR T1 - The deubiquitylase USP9X controls ribosomal stalling JF - bioRxiv DO - 10.1101/2020.04.15.042291 SP - 2020.04.15.042291 AU - Anne Clancy AU - Claire Heride AU - Adán Pinto-Fernández AU - Andreas Kallinos AU - Katherine J. Kayser-Bricker AU - Weiping Wang AU - Victoria Smith AU - Hannah Elcocks AU - Simon Davis AU - Shawn Fessler AU - Crystal McKinnon AU - Marie Katz AU - Tim Hammonds AU - Neil P. Jones AU - Jonathan O’Connell AU - Bruce Follows AU - Steven Mischke AU - Justin A. Caravella AU - Stephanos Ioannidis AU - Christopher Dinsmore AU - Sunkyu Kim AU - Axel Behrens AU - David Komander AU - Benedikt M. Kessler AU - Sylvie Urbé AU - Michael J. Clague Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/04/16/2020.04.15.042291.abstract N2 - 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.Competing Interest StatementThe authors have declared no competing interest. ER -