title: Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response.
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.
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.
authors.forename: David W
authors.initials: DW
authors.lastname: Reid
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.
authors.forename: Angeline S L
authors.initials: AS
authors.lastname: Tay
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.
authors.forename: Jeyapriya R
authors.initials: JR
authors.lastname: Sundaram
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.
authors.forename: Irene C J
authors.initials: IC
authors.lastname: Lee
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore.
authors.forename: Simi E
authors.initials: SE
authors.lastname: George
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Nicchitta
authors.affiliation: Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore Signature Research Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore, Singapore shirish.shenolikar@duke-nus.edu.sg.
authors.forename: Shirish
authors.initials: S
authors.lastname: Shenolikar
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D015852:Eukaryotic Initiation Factor-2; D008565:Membrane Proteins; C513256:Ppp1r15a protein, mouse; C480350:Ppp1r15b protein, mouse; D054645:Protein Phosphatase 1