Ribosome-associated chaperone DNAJC2 titrates translation flux to alleviate the burden of co-translational quality control

Ribosome collisions during aberrant translation activate ribosome-associated quality control (RQC) to resolve stalled ribosome complexes and triage incomplete nascent chains. How this co-translational surveillance is coordinated with other ribosome-associated activities remains unclear. Here, we identify the ribosome-associated Hsp40 chaperone DNAJC2 that restrains translational flux and limits RQC engagement during collision-prone translation. Genetic epistasis analysis revealed that DNAJC2 titrates the flux of aberrant translation intermediates through the canonical RQC pathway, from the collision-sensing RQC factor ZNF598 to the downstream NEMF-LTN1 E3 ligase complex for proteasomal degradation. DNAJC2 depletion further sensitized cells to collision-induced ribotoxic stress response (RSR), indicating increased vulnerability to global translation stress. Mechanistically, loss of DNAJC2 accelerated translation elongation, thereby promoting ribosome collisions and ZNF598-dependent ribosome disassembly. Accordingly, reducing translational flux with the translation inhibitor homoharringtonine or a huntingtin upstream ORF rescued DNAJC2-depletion phenotypes during RQC-sensitive poly(A)-mediated translational stalling. Together, we propose that DNAJC2 acts as a translational rheostat to buffer ribosome collisions, prevent RQC overload, and set the threshold for RSR activation.