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The deubiquitylase USP9X controls ribosomal stalling

Clancy, A; Heride, C; Pinto-Fernandez, A; Elcocks, H; Kallinos, A; Kayser-Bricker, KJ; Wang, WP; Smith, V; Davis, S; Fessler, S; McKinnon, C; Katz, M; Hammonds, T; Jones, NP; O'Connell, J; Follows, B; Mischke, S; Caravella, JA; Ioannidis, S; Dinsmore, C; Kim, S; Behrens, A; Komander, D; Kessler, BM; Urbe, S; Clague, MJ


A Clancy

C Heride

A Pinto-Fernandez

H Elcocks

A Kallinos

KJ Kayser-Bricker

WP Wang

V Smith

S Davis

S Fessler

C McKinnon

M Katz

T Hammonds

NP Jones

J O'Connell

B Follows

S Mischke

JA Caravella

S Ioannidis

C Dinsmore

S Kim

A Behrens

D Komander

BM Kessler

S Urbe

MJ Clague


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 subunits of the ribosome. We have developed a specific small-molecule inhibitor of the deubiquitylase USP9X. Proteomics analysis, following inhibitor treatment of HCT116 cells, confirms previous reports linking USP9X with centrosome-associated protein stability but also reveals a loss of Makorin 2 and ZNF598. We show that USP9X interacts with both these ubiquitin E3 ligases, regulating their abundance through the control of protein stability. In the absence of USP9X or following chemical inhibition of its catalytic activity, levels of Makorins and ZNF598 are diminished, and the ribosomal quality control pathway is impaired.


Clancy, A., Heride, C., Pinto-Fernandez, A., Elcocks, H., Kallinos, A., Kayser-Bricker, K., …Clague, M. (2021). The deubiquitylase USP9X controls ribosomal stalling. Journal of Cell Biology, 220(3),

Journal Article Type Article
Acceptance Date Dec 11, 2020
Publication Date 2021
Deposit Date Jan 11, 2022
Publicly Available Date Jan 11, 2022
Print ISSN 0021-9525
Publisher Rockefeller University Press
Peer Reviewed Peer Reviewed
Volume 220
Issue 3
Public URL


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