Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response.
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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.
Eukaryotic Initiation Factor-2
Protein Phosphatase 1
Unfolded Protein Response
Published Version (Please cite this version)10.1128/mcb.00190-16
Publication InfoReid, David W; Tay, Angeline SL; Sundaram, Jeyapriya R; Lee, Irene CJ; Chen, Qiang; George, Simi E; ... Shenolikar, Shirish (2016). Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response. Molecular and cellular biology, 36(13). pp. 1868-1880. 10.1128/mcb.00190-16. Retrieved from https://hdl.handle.net/10161/17233.
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Christopher Vincent Nicchitta
Professor of Cell Biology
Our laboratory studies the cellular architecture and regulation of protein synthesis, with the goal of understanding how cells regulate the subcellular organization and temporal dynamics of protein synthesis. We focus on mRNA localization - the process by which cells control where and when a protein is synthesized by localizing its mRNA to a discrete location(s) in the cell. Such regulation is critical for many aspects of cell dynamics, cell signaling and cell division. Of the diverse mRN
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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