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Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1α complex to activate its deacetylase function.

dc.contributor.author Shenolikar, Shirish
dc.contributor.author Lee, Irene Chengjie
dc.contributor.author Ho, Xue Yan
dc.contributor.author George, Simi Elizabeth
dc.contributor.author Goh, Catherine Wenhui
dc.contributor.author Sundaram, Jeyapriya Rajameenakshi
dc.contributor.author Pang, Karen Ka Lam
dc.contributor.author Luo, Weiwei
dc.contributor.author Yusoff, Permeen
dc.contributor.author Sze, Newman Siu Kwan
dc.date.accessioned 2019-03-01T23:48:03Z
dc.date.available 2019-03-01T23:48:03Z
dc.date.issued 2018-02
dc.identifier cdd2017152
dc.identifier.issn 1350-9047
dc.identifier.issn 1476-5403
dc.identifier.uri https://hdl.handle.net/10161/18125
dc.description.abstract Phosphorylation of the eukaryotic translation initiation factor, eIF2α, by stress-activated protein kinases and dephosphorylation by the growth arrest and DNA damage-inducible protein (GADD34)-containing phosphatase is a central node in the integrated stress response. Mass spectrometry demonstrated GADD34 acetylation at multiple lysines. Substituting K315 and K322 with alanines or glutamines did not impair GADD34's ability to recruit protein phosphatase 1α (PP1α) or eIF2α, suggesting that GADD34 acetylation did not modulate eIF2α phosphatase activity. Arsenite (Ars)-induced oxidative stress increased cellular GADD34 levels and enhanced Sirtuin 1 (SIRT1) recruitment to assemble a cytoplasmic complex containing GADD34, PP1α, eIF2α and SIRT1. Induction of GADD34 in WT MEFs paralleled the dephosphorylation of eIF2α (phosphoserine-51) and SIRT1 (phosphoserine-47). By comparison, eIF2α and SIRT1 were persistently phosphorylated in Ars-treated GADD34-/- MEFs. Expressing WT GADD34, but not a mutant unable to bind PP1α in GADD34-/- MEFs restored both eIF2α and SIRT1 dephosphorylation. SIRT1 dephosphorylation increased its deacetylase activity, measured in vitro and in cells. Loss of function of GADD34 or SIRT1 enhanced cellular p-eIF2α levels and attenuated cell death following Ars exposure. These results highlighted a novel role for the GADD34/PP1α complex in coordinating the dephosphorylation and reactivation of eIF2α and SIRT1 to determine cell fate following oxidative stress.
dc.language eng
dc.publisher Springer Nature
dc.relation.ispartof Cell death and differentiation
dc.relation.isversionof 10.1038/cdd.2017.152
dc.subject Science & Technology
dc.subject Life Sciences & Biomedicine
dc.subject Biochemistry & Molecular Biology
dc.subject Cell Biology
dc.subject UNFOLDED PROTEIN RESPONSE
dc.subject ENDOPLASMIC-RETICULUM
dc.subject CELL-SURVIVAL
dc.subject DNA-DAMAGE
dc.subject INSULIN-RESISTANCE
dc.subject GADD34 PROTEIN
dc.subject 26S PROTEASOME
dc.subject PHOSPHORYLATION
dc.subject EIF2-ALPHA
dc.subject ACETYLATION
dc.title Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1α complex to activate its deacetylase function.
dc.type Journal article
dc.date.updated 2019-03-01T23:47:46Z
pubs.begin-page 255
pubs.end-page 267
pubs.issue 2
pubs.organisational-group School of Medicine
pubs.organisational-group Duke
pubs.organisational-group Psychiatry & Behavioral Sciences, Translational Neuroscience
pubs.organisational-group Psychiatry & Behavioral Sciences
pubs.organisational-group Clinical Science Departments
pubs.publication-status Published
pubs.volume 25
duke.contributor.orcid Shenolikar, Shirish|0000-0003-0540-6328


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