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bioRxiv · 10.64898/2026.04.23.720364

USP9X promotes the degradation of trapped translation factors on collided ribosomes

Teodorowicz, W.·Gurzeler, L.-A.·Muehlemann, O.
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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. Additionally to the previously identified factors GCN1, RNF14, and RNF25, we identify here the deubiquitinase USP9X as a regulator of this pathway. In the absence of USP9X deubiquitinase activity, eRF1 is still ubiquitinated but fails to undergo efficient degradation. However, compared to wildtype cells, K6-linked ubiquitin chains accumulate on eRF1 in cells lacking USP9X activity, suggesting that USP9X trims K6-linked ubiquitin chains during a late step of substrate processing. Furthermore, clearance of trapped eRF1 engages a feedback mechanism involving 4EHP and the integrated stress response (ISR) to suppress translation, whereas impaired degradation prevents translational shutdown.

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Teodorowicz, W., Gurzeler, L.-A., Muehlemann, O.. 2026-04-23. USP9X promotes the degradation of trapped translation factors on collided ribosomes. https://doi.org/10.64898/2026.04.23.720364

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