USP9X promotes the degradation of trapped translation factors on collided ribosomes

ABSTRACT: Various ribosome-associated quality control pathways safeguard translation fidelity by detecting and resolving aberrant translation events. Recently, a pathway that senses stalled ribosomes with an occluded A-site has been described. The small molecules NVS1.1 and Ternatin-4 induce ribosome stalling by trapping eRF1 and eEF1A1, respectively, within the ribosomal A-site, thereby promoting their ubiquitination and proteasomal degradation. Here, in addition to the previously identified factors GCN1, RNF14, and RNF25, we identify the deubiquitinase USP9X as a regulator of this pathway. USP9X is required for efficient clearance of A-site–trapped proteins and regulates K6-linked ubiquitination of eRF1, a modification associated with VCP-dependent substrate processing. In the absence of USP9X activity, K6-linked ubiquitinated eRF1 accumulates, suggesting defective ubiquitin-chain remodeling and impaired downstream degradation. Furthermore, clearance of trapped translation factors engages a feedback mechanism involving 4EHP and the integrated stress response (ISR) to suppress translation, whereas impaired degradation prevents efficient translational shutdown.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Embryonic Kidney Cell Line, Hek-293 Cell

SUBMITTER: Manfred Heller  

LAB HEAD: Oliver Mühlemann

PROVIDER: PXD079916 | Pride | 2026-09-22

REPOSITORIES: Pride