Work

USP9X promotes the degradation of trapped translation factors on collided ribosomes

Year: 2026

Type: article

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 eukaryotic release factor 1 (eRF1) and elongation factor 1A1 (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 with wild-type 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.

Source: Cell Reports

DOI: 10.1016/j.celrep.2026.118125

Authors: Wojciech Teodorowicz, Lukas-Adrian Gurzeler, Oliver Mühlemann

Institution: University of Bern

Language: English

Topic: RNA and protein synthesis mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $5,620

Funders: University of Bern, Kanton Bern, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, NCCR Catalysis