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.

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