Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 30, Issue 8, Pages 2006-2016Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01350-09
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Funding
- National Institutes of Health [R01 AI069000, R01 CA140445]
- Damon Runyon Cancer Research Foundation
- Deutsche Forschungsgemeinschaft [SCHU 2294/2-1]
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Cells possess mechanisms that permit survival and recovery from stress, several of which regulate the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2 alpha). We identified the human OGFOD1 protein as a novel stress granule component that regulates the phosphorylation of eIF2 alpha and the resumption of translation in cells recovering from arsenite-induced stress. Coimmunoprecipitation studies revealed that OGFOD1 associates with a small subset of stress granule proteins (G3BP1, USP10, Caprin1, and YB-1) and the ribosome in both unstressed and stressed cells. Overexpression of OGFOD1 led to increased abundance of phosphorylated eIF2 alpha, both in unstressed cells and in cells exposed to arsenite-induced stress, and to accelerated apoptosis during stress. Conversely, knockdown of OGFOD1 resulted in smaller amounts of phosphorylated eIF2 alpha and a faster accumulation of polyribosomes in cells recovering from stress. Finally, OGFOD1 interacted with both eIF2 alpha and the eIF2 alpha kinase heme-regulated inhibitor (HRI), which was identified as a novel stress granule resident. These findings argue that OGFOD1 plays important proapoptotic roles in the regulation of translation and HRI-mediated phosphorylation of eIF2 alpha in cells subjected to arsenite-induced stress.
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