Ribosome-associated quality control (RQC) pathways protect cells from toxicity caused by incomplete protein products resulting from translation of damaged or problematic mRNAs. Extensive work in yeast has identified highly conserved mechanisms that lead to degradation of faulty mRNA and partially synthesized polypeptides. Here we used CRISPR-Cas9-based screening to search for additional RQC strategies in mammals. We found that failed translation leads to specific inhibition of translation initiation on that message. This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP. Model substrates and growth-based assays established that inhibition of additional rounds of translation acts in concert with known RQC pathways to prevent buildup of toxic proteins. Inability to block translation of faulty mRNAs and subsequent accumulation of partially synthesized polypeptides could explain the neurodevelopmental and neuropsychiatric disorders observed in mice and humans with compromised GIGYF2 function.

核糖体相关质量控制 (RQC) 途径可保护细胞免受由受损或有问题的 mRNA 翻译产生的不完整蛋白质产物引起的毒性。在酵母中进行的大量工作已经确定了导致错误 mRNA 和部分合成多肽降解的高度保守机制。在这里，我们使用基于 CRISPR-Cas9 的筛选来寻找哺乳动物中的其他 RQC 策略。我们发现失败的翻译会导致对该消息的翻译启动的特定抑制。这种负反馈环由两种翻译抑制剂 GIGYF2 和 4EHP 介导。模型底物和基于生长的测定证实，抑制额外的翻译轮次与已知的 RQC 途径协同作用，可防止有毒蛋白质的积累。无法阻断有缺陷的 mRNA 的翻译以及随后部分合成的多肽的积累可以解释在 GIGYF2 功能受损的小鼠和人类中观察到的神经发育和神经精神疾病。