Ribosome quality control antagonizes the activation of the integrated stress response on colliding ribosomes

Stalling during translation triggers ribosome quality control (RQC) to maintain proteostasis. Recently, stalling has also been linked to the activation of integrated stress response (ISR) by Gcn2. How the two processes are coordinated is unclear. Here, we show that activation of RQC by Hel2 suppresses that of Gcn2. We further show that Hel2 and Gcn2 are activated by a similar set of agents that cause ribosome stalling, with maximal activation of Hel2 observed at a lower frequency of stalling. Interestingly, inactivation of one pathway was found to result in the overactivation of the other, suggesting that both are activated by the same signal of ribosome collisions. Notably, the processes do not appear to be in direct competition with each other; ISR prefers a vacant A site, whereas RQC displays no preference. Collectively, our findings provide important details about how multiple pathways that recognize stalled ribosomes coordinate to mount the appropriate response.

Automated summary

Translation stalling activates ribosome quality control (RQC) and is linked to the integrated stress response (ISR) through Gcn2, with Hel2 suppressing Gcn2 activation. Both pathways are activated by similar factors causing ribosome stalling, although Hel2 is maximally activated at a lower frequency. Inactivation of one pathway leads to overactivation of the other, suggesting they are both triggered by the same signal. ISR prefers an empty A site while RQC shows no preference, indicating they do not directly compete with each other.