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

• Published in: Molecular cell Vol. 81; no. 3; pp. 614 - 628.e4
• Main Authors: Yan, Liewei L., Zaher, Hani S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04-02-2021
• Subjects: alkylation; Eukaryotic Initiation Factor-2 - genetics; Eukaryotic Initiation Factor-2 - metabolism; Gcn2; Hel2; integrated stress response; Peptide Elongation Factors - genetics; Peptide Elongation Factors - metabolism; Protein Biosynthesis; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; ribosome quality control; ribosome rescue; Ribosomes - genetics; Ribosomes - metabolism; RNA damage; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Stress, Physiological - genetics; Time Factors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Gcn2; Hel2; ribosome quality control; ribosome rescue; RNA damage; alkylation; integrated stress response
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2020.11.033

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.
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•Hel2 attenuates Gcn2-mediated activation of integrated stress response and vice versa•Gcn2 is activated in response to conditions that promote ribosome collisions•Stalling-induced integrated stress response prefers ribosomes with empty A sites•Hel2-mediated ubiquitination is more sensitive to stalling relative to Gcn2 activation
Ribosome stalling activates ribosome quality control (RQC) and integrated stress response, but how the two process are coordinated is unclear. Yan and Zaher show that although both processes are activated in response to ribosome collisions, RQC is more sensitive to changes to translation dynamics and responds quickly to lower collision frequency.