Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation

Elife. 2015 Mar 16;4:e04872. doi: 10.7554/eLife.04872.


Four stress-sensing kinases phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) to activate the integrated stress response (ISR). In animals, the ISR is antagonised by selective eIF2α phosphatases comprising a catalytic protein phosphatase 1 (PP1) subunit in complex with a PPP1R15-type regulatory subunit. An unbiased search for additional conserved components of the PPP1R15-PP1 phosphatase identified monomeric G-actin. Like PP1, G-actin associated with the functional core of PPP1R15 family members and G-actin depletion, by the marine toxin jasplakinolide, destabilised the endogenous PPP1R15A-PP1 complex. The abundance of the ternary PPP1R15-PP1-G-actin complex was responsive to global changes in the polymeric status of actin, as was its eIF2α-directed phosphatase activity, while localised G-actin depletion at sites enriched for PPP1R15 enhanced eIF2α phosphorylation and the downstream ISR. G-actin's role as a stabilizer of the PPP1R15-containing holophosphatase provides a mechanism for integrating signals regulating actin dynamics with stresses that trigger the ISR.

Keywords: CReP; D. melanogaster; GADD34; PPP1R15A; PPP1R15B; actin; biochemistry; cell biology; human; integrated stress response; mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Amino Acid Sequence
  • Animals
  • Conserved Sequence
  • Depsipeptides / pharmacology
  • Drosophila melanogaster
  • Eukaryotic Initiation Factor-2 / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Molecular Sequence Data
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Phosphatase 1 / chemistry
  • Stress, Physiological* / drug effects


  • Actins
  • Depsipeptides
  • Eukaryotic Initiation Factor-2
  • jasplakinolide
  • PPP1R15A protein, human
  • Protein Phosphatase 1