OGFOD1, a Novel Modulator of Eukaryotic Translation Initiation Factor 2α Phosphorylation and the Cellular Response to Stress

Abstract

Cells possess mechanisms that permit survival and recovery from stress, several of which regulate the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). We identified the human OGFOD1 protein as a novel stress granule component that regulates the phosphorylation of eIF2α 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 eIF2α, 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 eIF2α and a faster accumulation of polyribosomes in cells recovering from stress. Finally, OGFOD1 interacted with both eIF2α and the eIF2α 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 eIF2α in cells subjected to arsenite-induced stress.

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We are grateful to Karla Kirkegaard and Christopher J. Potter for critical readings of the manuscript. We also thank Joan A. Steitz for the kind gift of the Y10B antibody and Duncan Brown for the design of the USP10 siRNA.

This work was supported by National Institutes of Health grants R01 AI069000 and R01 CA140445 (to P.S.). K.A.W. was supported by a postdoctoral fellowship from the Damon Runyon Cancer Research Foundation. S.S. was supported by Deutsche Forschungsgemeinschaft postdoctoral fellowship SCHU 2294/2-1.