@article{72c5bafd873b4406acd7c37ff96182af,
title = "Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate",
abstract = "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.",
keywords = "SAPK, UV radiation, ZAK, amino acid starvation, integrated stress response, ribosome collisions",
author = "Wu, {Colin Chih Chien} and Amy Peterson and Boris Zinshteyn and Sergi Regot and Rachel Green",
note = "Funding Information: We thank Jamie Wangen, Niladri Sinha, and Kamena Kostova for critical reading; Andrew Holland for Flp-In T-REx HeLa cells; Thomas Tuschl for ZNF598 knockout cells; Christopher Shoemaker for advice on CRISPR screens; David Mohr and the Johns Hopkins Genetic Resources Core Facility for sequencing assistance; Jeff Corden for discussions. This work was supported by NIH ( R37GM059425 to R.G.) and HHMI (to R.G. and C.C.-C.W.). B.Z. is an HHMI fellow of the Damon Runyon Cancer Research Foundation ( DRG-2250-16 ). S.R. is supported by an NSF CAREER award ( MCB-1844994 ), NIGMS R35 ( 1R35GM133499 ), American Cancer Society Research Scholar Grant ( 133537-RSG-19-005-01-CCG ), and a Jerome L. Greene Foundation Discovery Award . Funding Information: We thank Jamie Wangen, Niladri Sinha, and Kamena Kostova for critical reading; Andrew Holland for Flp-In T-REx HeLa cells; Thomas Tuschl for ZNF598 knockout cells; Christopher Shoemaker for advice on CRISPR screens; David Mohr and the Johns Hopkins Genetic Resources Core Facility for sequencing assistance; Jeff Corden for discussions. This work was supported by NIH (R37GM059425 to R.G.) and HHMI (to R.G. and C.C.-C.W.). B.Z. is an HHMI fellow of the Damon Runyon Cancer Research Foundation (DRG-2250-16). S.R. is supported by an NSF CAREER award (MCB-1844994), NIGMS R35 (1R35GM133499), American Cancer Society Research Scholar Grant (133537-RSG-19-005-01-CCG), and a Jerome L. Greene Foundation Discovery Award. C.C.-C.W. and A.P. conducted the experimental work with assistance from B.Z. S.R. helped conceive the work. R.G. conceived and supervised the work. C.C.-C.W. and R.G. wrote the manuscript with input from A.P. B.Z. and S.R. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = jul,
day = "23",
doi = "10.1016/j.cell.2020.06.006",
language = "English (US)",
volume = "182",
pages = "404--416.e14",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",
}