Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate

Colin Chih-Chien Wu; Amy Peterson; Boris Zinshteyn; Sergi Regot; Rachel Green

doi:10.1016/j.cell.2020.06.006

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. Epub 2020 Jun 30.

Authors

Colin Chih-Chien Wu¹, Amy Peterson², Boris Zinshteyn¹, Sergi Regot², Rachel Green³

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].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

ATP-Binding Cassette Transporters / metabolism
Anisomycin / pharmacology
Apoptosis / drug effects
DNA Damage / radiation effects
Enzyme Activation
Humans
MAP Kinase Kinase Kinases / deficiency
MAP Kinase Kinase Kinases / genetics
MAP Kinase Kinase Kinases / metabolism
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 14 / metabolism
Phosphorylation
Polyribosomes / metabolism
Protein Isoforms / deficiency
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
RNA Interference
RNA, Messenger / metabolism
RNA, Small Interfering / metabolism
Ribosomes / metabolism*
Signal Transduction
Stress, Physiological*
Ultraviolet Rays
eIF-2 Kinase / metabolism

Substances

ABCF3 protein, human
ATP-Binding Cassette Transporters
Protein Isoforms
RNA, Messenger
RNA, Small Interfering
Anisomycin
EIF2AK4 protein, human
Protein Serine-Threonine Kinases
eIF-2 Kinase
Mitogen-Activated Protein Kinase 14
MAP Kinase Kinase Kinases
MAP3K20 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding