Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure.
Exposure to arsenite inhibits protein synthesis and activates multiple stress signaling pathways. Although arsenite has diverse effects on cell metabolism, we demonstrated that phosphorylation of eukaryotic translation initiation factor 2 at Ser-51 on the alpha subunit was necessary to inhibit protein synthesis initiation in arsenite-treated cells and was essential for stress granule formation. Of the four protein kinases known to phosphorylate eukaryotic translation initiation factor 2alpha, only the heme-regulated inhibitor kinase (HRI) was required for the translational inhibition in response to arsenite treatment in mouse embryonic fibroblasts. In addition, HRI expression was required for stress granule formation and cellular survival after arsenite treatment. In vivo studies elucidated a fundamental requirement for HRI in murine survival upon acute arsenite exposure. The results demonstrated an essential role for HRI in mediating arsenite stress-induced phosphorylation of eukaryotic translation initiation factor 2alpha, inhibition of protein synthesis, stress granule formation, and survival.
McEwen
Edward
E
Howard Hughes Medical Institute and the Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor 48109, USA.
Kedersha
Nancy
N
Song
Benbo
B
Scheuner
Donalyn
D
Gilks
Natalie
N
Han
Anping
A
Chen
Jane-Jane
JJ
Anderson
Paul
P
Kaufman
Randal J
RJ
D000818:Animals; D018053:Arsenites; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006418:Heme / Q000737:chemistry*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013723:Teratogens; D013997:Time Factors; D019892:eIF-2 Kinase / Q000378:metabolism / Q000502:physiology*
D018053:Arsenites; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; D013723:Teratogens; D006418:Heme; D019892:eIF-2 Kinase; C015001:arsenite