Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation
Joseph E Chambers,
Lucy E Dalton,
Hanna J Clarke,
Elke Malzer,
Caia S Dominicus,
Vruti Patel,
Greg Moorhead,
David Ron,
Stefan J Marciniak
Affiliations
Joseph E Chambers
Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom
Lucy E Dalton
Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom
Hanna J Clarke
Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
Elke Malzer
Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom
Caia S Dominicus
Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom
Vruti Patel
Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom
Greg Moorhead
Department of Biological Sciences, University of Calgary, Calgary, Canada
Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
Wellcome Trust MRC Building, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
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.
