Choe, Y.-J.; Chan, T. Y. K.; Choo, W. Y. X.; Yoon, M.-J.

Ribosomes translating damaged mRNAs can stall, producing incomplete and potentially toxic polypeptides. The ribosome-associated quality control (RQC) pathway, triggered by collisions between stalled and trailing ribosomes, eliminates these aberrant translation products. Upon collision, ribosomes are split, and nascent polypeptides remaining on the large subunit are polyubiquitylated for proteasomal degradation. However, recent studies have shown that translation elongation rates vary along normal transcripts, leading to widespread ribosome collisions. Here, we investigated whether RQC is regulated to prevent unnecessary protein degradation during transient ribosome collisions. Using multiple conditions that induce transient ribosome pausing, including mild amino acid limitation, short polyadenosine tracts, and delayed translation termination in [PSI+] yeast cells, we show that the Gcn1-Gcn20 complex, a co-activator of the integrated stress response (ISR) kinase Gcn2, inhibits RQC initiation. We therefore propose that the Gcn1-Gcn20 complex has a dual role in ribosome collision responses: activating the ISR while inhibiting RQC. When this complex is impaired, physiological translation becomes more susceptible to RQC.