Ribosome-quality control antagonizes the activation of the integrated-stress response on colliding ribosomes. Yan LL & Zaher HS

Ribosome stalling that occurs on aberrant mRNA activates quality-control pathways to maintain proteostasis. Recently, ribosome stalling has also been linked to the activation of Gcn2 and the subsequent integrated-stress response (ISR). How the two processes are coordinated is not completely clear. Here we show that activation of ribosome-quality control by Hel2 suppresses that of Gcn2 in yeast. In the absence of Hel2, we observe a gene-expression signature indicative of ISR activation, suggesting that the factor is used to suppress premature activation of Gcn2 in the absence of stress conditions. 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. Indeed, we provide evidence that suggests that, similar to Hel2, Gcn2 is activated by ribosome collisions. Notably, the processes do not appear to be in direct competition with each other; ISR was found to prefer the A site of the ribosome to be vacant, whereas RQC displays no preference as to the status of the A site. Collectively, our findings provide important details about how multiple pathways that recognize stalled ribosomes coordinate to mount the appropriate response.