Problems arising during translation of mRNAs lead to ribosome stalling and collisions that trigger a series of quality control events. However, the global cellular response to ribosome collisions has not been explored. Here, we uncover a function for ribosome collisions in signal transduction. Using translation elongation inhibitors and general cellular stress conditions, including amino acid starvation and UV irradiation, we show that ribosome collisions activate the stress-activated protein kinase (SAPK) and GCN2-mediated stress response pathways. We show that the MAPKKK ZAK functions as the sentinel for ribosome collisions and is required for immediate early activation of both SAPK (p38/JNK) and GCN2 signaling pathways. Selective ribosome profiling and biochemistry demonstrate that although ZAK generally associates with elongating ribosomes on polysomal mRNAs, it specifically auto-phosphorylates on the minimal unit of colliding ribosomes, the disome. Together, these results provide molecular insights into how perturbation of translational homeostasis regulates cell fate.

mRNA 翻译过程中出现的问题会导致核糖体停滞和碰撞，从而触发一系列质量控制事件。然而，尚未探索全球细胞对核糖体碰撞的反应。在这里，我们发现了信号转导中核糖体碰撞的功能。使用翻译延伸抑制剂和一般细胞应激条件（包括氨基酸饥饿和紫外线照射），我们发现核糖体碰撞激活应激激活蛋白激酶（SAPK）和 GCN2 介导的应激反应途径。我们发现 MAPKKK ZAK 充当核糖体碰撞的哨兵，并且是 SAPK (p38/JNK) 和 GCN2 信号通路立即早期激活所必需的。选择性核糖体分析和生物化学表明，虽然 ZAK 通常与多核糖体 mRNA 上的延长核糖体相关，但它在碰撞核糖体的最小单位（二体）上特异性地自动磷酸化。总之，这些结果为翻译稳态的扰动如何调节细胞命运提供了分子见解。