Journal
CELL
Volume 182, Issue 2, Pages 404-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.06.006
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Funding
- NIH [R37GM059425]
- HHMI
- NSF CAREER award [MCB-1844994]
- NIGMS R35 [1R35GM133499]
- American Cancer Society Research Scholar Grant [133537-RSG-19-005-01-CCG]
- Jerome L. Greene Foundation Discovery Award
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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.
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