Arsenite and other environmental agents that cause protein malfolding promote eIF2a phosphorylation and activate the Integrated Stress Response. Arsenite activates the eIF2a kinase HRI in reticulocyte lysates by disrupting a repressive complex of chaperones (Lu, et al., 2001, Translation Initiation Control by Heme-Regulated Eukaryotic Initiation Factor 2alpha Kinase in Erythroid Cells under Cytoplasmic Stresses. Mol Cell Biol; 21:7971). A recent report indicates that arsenite treated HRI-/- cells and animals are ISR defective (McEwen, et al., 2005, Heme-regulated inhibitor (HRI) kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 (eIF2) inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure. J Biol Chem; 280:16925). However in our hands, HRI-/- cells (download data) (and PERK-/-, GCN2-/-, PKR-/- and compound PERK-/-;GCN2-/-, PERK-/-;PKR-/- and PKR-/-;GCN2-/- cells, data not shown) are all able to phosphorylate eIF2a and activate the ISR when treated with arsenite (see below the data for HRI). HRI may well play a special role in phosphorylating eIF2a in arsenite-treated cells and in some cells and under some conditions (such as those tested by McEwen and colleagues) HRI’s role may even be essential. However, our observations indicate that no single known eIF2a kinase is absolutely required for phosphorylation of the translation initiation factor in arsenite-treated cells. eIF2a kinases have an exceptionally long loop between kinase domains IV and V, rendering them identifiable by homology searches and the annotated genomic sequence of several mammalian species (which has become available in recent years), does not suggest the existence of other eIF2a kinases. Therefore, while the existence of an undiscovered arsenite-activated eIF2a kinase(s) cannot be excluded, the weight of the evidence suggests that other mechanisms need to be considered.

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David Ron
NYU School of Medicine
May 18, 2005