OGFOD1, a novel modulator of eukaryotic translation initiation factor 2alpha phosphorylation and the cellular response to stress.
Cells possess mechanisms that permit survival and recovery from stress, several of which regulate the phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha). We identified the human OGFOD1 protein as a novel stress granule component that regulates the phosphorylation of eIF2alpha 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 eIF2alpha, 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 eIF2alpha and a faster accumulation of polyribosomes in cells recovering from stress. Finally, OGFOD1 interacted with both eIF2alpha and the eIF2alpha 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 eIF2alpha in cells subjected to arsenite-induced stress.
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USAA.
Karen A
KA
Wehner
Sylvia
S
Schütz
Peter
P
Sarnow
D000818:Animals; D017209:Apoptosis; D018053:Arsenites / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D000075223:Poly-ADP-Ribose Binding Proteins; D014176:Protein Biosynthesis / Q000187:drug effects; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013723:Teratogens / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism
D018053:Arsenites; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D009687:Nuclear Proteins; C548916:OGFOD1 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D034741:RNA, Small Interfering; D013723:Teratogens; C431363:USP10 protein, human; D019284:Thapsigargin; D043222:Ubiquitin Thiolesterase; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases; C015001:arsenite