2. Academic Validation
  3. Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate

Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate

  • Cell. 2020 Jul 23;182(2):404-416.e14. doi: 10.1016/j.cell.2020.06.006.
Colin Chih-Chien Wu 1,  Amy Peterson 2,  Boris Zinshteyn 1,  Sergi Regot 2,  Rachel Green 3
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 3 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: [email protected].
PMID: 32610081 DOI: 10.1016/j.cell.2020.06.006
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.

Figures