Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USAA.
Mol Cell Biol. 2010 Apr;30(8):2006-16. doi: 10.1128/MCB.01350-09. Epub 2010 Feb 12.
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.
细胞具有使其能够在压力下生存和恢复的机制，其中有几种机制可调节真核翻译起始因子 2alpha（eIF2alpha）的磷酸化。我们发现人类 OGFOD1 蛋白是一种新的应激颗粒成分，可调节 eIF2alpha 的磷酸化以及细胞从亚砷酸盐诱导的应激中恢复时翻译的恢复。共免疫沉淀研究表明，在未受应激和受应激的细胞中，OGFOD1 与应激颗粒蛋白（G3BP1、USP10、Caprin1 和 YB-1）和核糖体的一小部分结合。OGFOD1 的过表达导致未受应激的细胞和暴露于亚砷酸盐诱导的应激的细胞中磷酸化的 eIF2alpha 的丰度增加，并在应激期间加速凋亡。相反，OGFOD1 的敲低导致应激恢复细胞中磷酸化的 eIF2alpha 量减少，多核糖体的积累更快。最后，OGFOD1 与 eIF2alpha 和 eIF2alpha 激酶血红素调节抑制剂（HRI）相互作用，HRI 被鉴定为一种新的应激颗粒驻留蛋白。这些发现表明，OGFOD1 在调节受到亚砷酸盐诱导的应激的细胞中的翻译和 HRI 介导的 eIF2alpha 磷酸化中发挥重要的促凋亡作用。
