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

Phosphorylation of eukaryotic initiation factor 2 alpha (eIF2 alpha) controls transcriptome-wide changes in mRNA translation in stressed cells. While phosphorylated eIF2 alpha (P-eIF2 alpha) attenuates global protein synthesis, mRNAs encoding stress proteins are more efficiently translated. Two eIF2 alpha phosphatases, containing GADD34 and CReP, catalyze P-eIF2 alpha 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-eIF2 alpha 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, eIF2 alpha 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 eIF2 alpha phosphatases to control cell viability.