Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1α complex to activate its deacetylase function.
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.
Type
Journal articleSubject
Science & TechnologyLife Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
UNFOLDED PROTEIN RESPONSE
ENDOPLASMIC-RETICULUM
CELL-SURVIVAL
DNA-DAMAGE
INSULIN-RESISTANCE
GADD34 PROTEIN
26S PROTEASOME
PHOSPHORYLATION
EIF2-ALPHA
ACETYLATION
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https://hdl.handle.net/10161/18125Published Version (Please cite this version)
10.1038/cdd.2017.152Publication Info
Shenolikar, Shirish; Lee, Irene Chengjie; Ho, Xue Yan; George, Simi Elizabeth; Goh,
Catherine Wenhui; Sundaram, Jeyapriya Rajameenakshi; ... Sze, Newman Siu Kwan (2018). Oxidative stress promotes SIRT1 recruitment to the GADD34/PP1α complex to activate
its deacetylase function. Cell death and differentiation, 25(2). pp. 255-267. 10.1038/cdd.2017.152. Retrieved from https://hdl.handle.net/10161/18125.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Shirish Shenolikar
Professor Emeritus of Psychiatry and Behavioral Sciences
Protein phosphorylation controls a wide range of physiological processes in mammalian
tissues. Phosphorylation state of cellular proteins is controlled by the opposing
actions of protein kinases and phosphatases that are regulated by hormones, neurotransmitters,
growth factors and other environmental cues. Our research attempts to understand the
communication between protein kinases and phosphatases that dictates cellular protein
phosphorylation and the cell's response to hormones. Over the

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