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dc.contributor.authorChambers, Josephen
dc.contributor.authorDalton, Lucy Een
dc.contributor.authorClarke, Hanna Jen
dc.contributor.authorMalzer, Elkeen
dc.contributor.authorDominicus, Caia Sen
dc.contributor.authorPatel, Vrutien
dc.contributor.authorMoorhead, Gregen
dc.contributor.authorRon, Daviden
dc.contributor.authorMarciniak, Stefanen
dc.date.accessioned2015-05-26T13:50:24Z
dc.date.available2015-05-26T13:50:24Z
dc.date.issued2015-03-16en
dc.identifier.citationeLife 2015 4: e04872. DOI: 10.7554/eLife.04872en
dc.identifier.issn2050-084X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/247986
dc.description.abstractFour 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.
dc.description.sponsorshipThis work was funded by the Medical Research Council (UK) (MRC Ref G1002610) and a Wellcome Trust Strategic Award for core facilities to the Cambridge Institute for Medical Research (CIMR, Wellcome 100140). SJM holds a Senior Clinical Research Fellowship from the Medical Research Council (MRC Ref G1002610). DR is a Wellcome Trust Principal Research Fellow (Wellcome 084812/Z/08/Z). The June Hancock Mesothelioma Research Fund funded LED (JH09-2); the British Lung Foundation funded HJC (APHD11-4); CD is a member of the CIMR PhD programme funded by the Wellcome Trust; and VP holds a Diabetes UK Arthur and Sadie Pethybridge PhD Studentship.
dc.languageEnglishen
dc.language.isoenen
dc.publishereLife
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.titleActin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylationen
dc.typeArticle
dc.description.versionThis is the final published version. It first appeared at http://elifesciences.org/content/4/e04872.en
prism.numbere04872en
prism.publicationDate2015en
prism.publicationNameeLIFEen
prism.volume4en
dc.rioxxterms.funderMRC
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.projectidG1002610
dc.rioxxterms.projectid084812/Z/08/Z
dc.rioxxterms.projectid100140
dcterms.dateAccepted2015-03-12en
rioxxterms.versionofrecord10.7554/eLife.04872en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-03-16en
dc.contributor.orcidChambers, Joseph [0000-0003-4675-0053]
dc.contributor.orcidRon, David [0000-0002-3014-5636]
dc.contributor.orcidMarciniak, Stefan [0000-0001-8472-7183]
dc.identifier.eissn2050-084X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (084812/Z/08/Z)
pubs.funder-project-idMRC (G1002610)
pubs.funder-project-idMedical Research Council (MR/M010392/1)
pubs.funder-project-idMRC (G0601840)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
pubs.funder-project-idDiabetes UK (12/0004595)
pubs.funder-project-idWorldwide Cancer Research (14-1069)


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales