O-GlcNAc modification of eIF4GI acts as a translational switch in heat shock response

Nat Chem Biol. 2018 Oct;14(10):909-916. doi: 10.1038/s41589-018-0120-6. Epub 2018 Aug 20.

Abstract

Heat shock response (HSR) is an ancient signaling pathway leading to thermoprotection of nearly all living organisms. Emerging evidence suggests that intracellular O-linked β-N-acetylglucosamine (O-GlcNAc) serves as a molecular 'thermometer' by reporting ambient temperature fluctuations. Whether and how O-GlcNAc modification regulates HSR remains unclear. Here we report that, upon heat shock stress, the key translation initiation factor eIF4GI undergoes dynamic O-GlcNAcylation at the N-terminal region. Without O-GlcNAc modification, the preferential translation of stress mRNAs is impaired. Unexpectedly, stress mRNAs are entrapped within stress granules (SGs) that are no longer dissolved during stress recovery. Mechanistically, we show that stress-induced eIF4GI O-GlcNAcylation repels poly(A)-binding protein 1 and promotes SG disassembly, thereby licensing stress mRNAs for selective translation. Using various eIF4GI mutants created by CRISPR/Cas9, we demonstrate that eIF4GI acts as a translational switch via reversible O-GlcNAcylation. Our study reveals a central mechanism linking heat stress sensing, protein remodeling, SG dynamics and translational reprogramming.

MeSH terms

  • Acetylglucosamine / chemistry*
  • Animals
  • CRISPR-Cas Systems
  • Cytoplasm
  • Eukaryotic Initiation Factor-4G / chemistry*
  • Fibroblasts / metabolism
  • Glycosylation
  • HSP70 Heat-Shock Proteins / chemistry
  • Heat-Shock Response*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mice
  • N-Acetylglucosaminyltransferases / chemistry*
  • Protein Domains
  • Protein Processing, Post-Translational*
  • Proteins
  • Signal Transduction
  • Stress, Mechanical
  • Temperature

Substances

  • EIF4G1 protein, human
  • Eif4g1 protein, mouse
  • Eukaryotic Initiation Factor-4G
  • HSP70 Heat-Shock Proteins
  • Proteins
  • N-Acetylglucosaminyltransferases
  • Acetylglucosamine