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Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response.

dc.contributor.author Chen, Qiang
dc.contributor.author George, Simi E
dc.contributor.author Lee, Irene CJ
dc.contributor.author Nicchitta, Christopher
dc.contributor.author Reid, David W
dc.contributor.author Shenolikar, Shirish
dc.contributor.author Sundaram, Jeyapriya R
dc.contributor.author Tay, Angeline SL
dc.date.accessioned 2018-07-16T17:02:14Z
dc.date.available 2018-07-16T17:02:14Z
dc.date.issued 2016-07
dc.identifier.issn 0270-7306
dc.identifier.issn 1098-5549
dc.identifier.uri https://hdl.handle.net/10161/17233
dc.description.abstract Phosphorylation of eukaryotic initiation factor 2α (eIF2α) controls transcriptome-wide changes in mRNA translation in stressed cells. While phosphorylated eIF2α (P-eIF2α) attenuates global protein synthesis, mRNAs encoding stress proteins are more efficiently translated. Two eIF2α phosphatases, containing GADD34 and CReP, catalyze P-eIF2α dephosphorylation. The current view of GADD34, whose transcription is stress induced, is that it functions in a feedback loop to resolve cell stress. In contrast, CReP, which is constitutively expressed, controls basal P-eIF2α levels in unstressed cells. Our studies show that GADD34 drives substantial changes in mRNA translation in unstressed cells, particularly targeting the secretome. Following activation of the unfolded protein response (UPR), rapid translation of GADD34 mRNA occurs and GADD34 is essential for UPR progression. In the absence of GADD34, eIF2α phosphorylation is persistently enhanced and the UPR translational program is significantly attenuated. This "stalled" UPR is relieved by the subsequent activation of compensatory mechanisms that include AKT-mediated suppression of PKR-like kinase (PERK) and increased expression of CReP mRNA, partially restoring protein synthesis. Our studies highlight the coordinate regulation of UPR by the GADD34- and CReP-containing eIF2α phosphatases to control cell viability.
dc.language eng
dc.publisher AMER SOC MICROBIOLOGY
dc.relation.ispartof Molecular and cellular biology
dc.relation.isversionof 10.1128/mcb.00190-16
dc.subject Cells, Cultured
dc.subject Fibroblasts
dc.subject Animals
dc.subject Mice
dc.subject Membrane Proteins
dc.subject Eukaryotic Initiation Factor-2
dc.subject Cell Survival
dc.subject Protein Biosynthesis
dc.subject Phosphorylation
dc.subject Protein Phosphatase 1
dc.subject Unfolded Protein Response
dc.title Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response.
dc.type Journal article
dc.date.updated 2018-07-16T17:02:11Z
pubs.begin-page 1868
pubs.end-page 1880
pubs.issue 13
pubs.organisational-group School of Medicine
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Biochemistry
pubs.organisational-group Basic Science Departments
pubs.organisational-group Cell Biology
pubs.organisational-group Pathology
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Psychiatry & Behavioral Sciences, Translational Neuroscience
pubs.organisational-group Psychiatry & Behavioral Sciences
pubs.publication-status Published
pubs.volume 36
duke.contributor.orcid Shenolikar, Shirish|0000-0003-0540-6328


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