Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response.
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2016-07
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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.
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Reid, David W, Angeline SL Tay, Jeyapriya R Sundaram, Irene CJ Lee, Qiang Chen, Simi E George, Christopher V Nicchitta, Shirish Shenolikar, et al. (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
From the ER to Stress Granules: Defining Pathways of RNA Regulation:
Our laboratory investigates how cells control the location and timing of protein synthesis, with a focus on mRNA localization—the process by which mRNAs are targeted to specific sites within the cell to direct protein production. This spatial and temporal regulation is essential for cell signaling, division, and overall cellular dynamics.
We study mRNA localization to the endoplasmic reticulum (ER), where this process occurs on an unusually large scale. While the ER has long been recognized as the translation site for mRNAs encoding secretory and membrane proteins, our research has revealed that the ER functions far more broadly, supporting translation across the transcriptome. In particular, we have shown that newly exported mRNAs are preferentially translated on the ER, a process we hypothesize is coupled to RNA quality-control mechanisms during the pioneer rounds of translation.
Our recent work has also uncovered links between ER-directed mRNA localization and the pathways governing stress granule (SG) biogenesis. We are currently investigating how transcriptional status influences mRNA recruitment into SGs, the mechanisms that determine which mRNAs are selected, and the role of ER-associated sites in organizing SG assembly.
To address these questions, we combine biochemistry, cell biology, advanced imaging, genomics, and computational biology. Current research themes include:
- Cis-encoded signals and targeting mechanisms – defining mRNA sequence elements and cellular factors that direct ER localization. Beyond the canonical SRP pathway, our CRISPR/Cas studies have revealed additional, pathway-independent routes that recruit even cytosolic and nucleoplasmic mRNAs to the ER.
- RNA-binding proteins and stress responses – investigating how RNA-binding proteins mediate mRNA localization to the ER and regulate selective mRNA recruitment into SGs. Approaches include optical imaging, nucleoside analog pulse-labeling, cell fractionation, proteomics, ribosome footprinting, and RNA-seq methods (including 4SU-RNAseq).
Through these studies, our goal is to uncover fundamental principles of RNA regulation, quality control, and cellular organization.
Shirish Shenolikar
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 last decade, our work has provided critical information about the role of protein phosphatase-1 (PP1) in controlling synaptic function, cell stress, gene expression and growth. We have generated a large repertoire of reagents to decipher PP1's role in signaling pathways in mammalian cells and tissues. Emerging evidence suggests that in many cells, PP1 activity is fine tuned by the protein, inhibitor-1 (I-1). A major focus of our research is to elucidate the role of I-1 in kinase-phosphatase cross-talk and impact of the altered I-1 gene expression seen in several human diseases. Our studies showed that recognition of cellular substrates by PP1 is also directed by its association with a variety of targeting subunits that are themselves also subject to physiological control. Thus, the overall focus of our research is to define the physiological mechanisms that regulate PP1 functions relevant to human health and disease.
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