title: Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation.
abstract: 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.
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Chambers
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Dalton
authors.affiliation: Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Clarke
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Elke
authors.initials: E
authors.lastname: Malzer
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Caia S
authors.initials: CS
authors.lastname: Dominicus
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Vruti
authors.initials: V
authors.lastname: Patel
authors.affiliation: Department of Biological Sciences, University of Calgary, Calgary, Canada.
authors.forename: Greg
authors.initials: G
authors.lastname: Moorhead
authors.affiliation: Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom.
authors.forename: David
authors.identifier: http://orcid.org/0000-0002-3014-5636
authors.initials: D
authors.lastname: Ron
authors.affiliation: Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stefan J
authors.identifier: http://orcid.org/0000-0001-8472-7183
authors.initials: SJ
authors.lastname: Marciniak
mesh_terms: D000199:Actins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D047630:Depsipeptides / Q000494:pharmacology; D004331:Drosophila melanogaster; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000737:chemistry; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D000199:Actins; D047630:Depsipeptides; D015852:Eukaryotic Initiation Factor-2; C057531:jasplakinolide; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1
keywords: CReP; D. melanogaster; GADD34; PPP1R15A; PPP1R15B; actin; biochemistry; cell biology; human; integrated stress response; mouse