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Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate.
Cell. 2020 Jul 23; 182(2):404-416.e14.Cell

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.

Authors+Show Affiliations

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: ragreen@jhmi.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32610081

Citation

Wu, Colin Chih-Chien, et al. "Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate." Cell, vol. 182, no. 2, 2020, pp. 404-416.e14.
Wu CC, Peterson A, Zinshteyn B, et al. Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate. Cell. 2020;182(2):404-416.e14.
Wu, C. C., Peterson, A., Zinshteyn, B., Regot, S., & Green, R. (2020). Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate. Cell, 182(2), 404-e14. https://doi.org/10.1016/j.cell.2020.06.006
Wu CC, et al. Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate. Cell. 2020 Jul 23;182(2):404-416.e14. PubMed PMID: 32610081.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate. AU - Wu,Colin Chih-Chien, AU - Peterson,Amy, AU - Zinshteyn,Boris, AU - Regot,Sergi, AU - Green,Rachel, Y1 - 2020/06/30/ PY - 2020/02/26/received PY - 2020/05/18/revised PY - 2020/06/02/accepted PY - 2021/07/23/pmc-release PY - 2020/7/2/pubmed PY - 2020/7/2/medline PY - 2020/7/2/entrez KW - SAPK KW - UV radiation KW - ZAK KW - amino acid starvation KW - integrated stress response KW - ribosome collisions SP - 404 EP - 416.e14 JF - Cell JO - Cell VL - 182 IS - 2 N2 - 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. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/32610081/Ribosome_Collisions_Trigger_General_Stress_Responses_to_Regulate_Cell_Fate DB - PRIME DP - Unbound Medicine ER -
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