title: Phosphorylation of eukaryotic initiation factor 2 by heme-regulated inhibitor kinase-related protein kinases in Schizosaccharomyces pombe is important for fesistance to environmental stresses.
abstract: Protein synthesis is regulated by the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) in response to different environmental stresses. One member of the eIF2alpha kinase family, heme-regulated inhibitor kinase (HRI), is activated under heme-deficient conditions and blocks protein synthesis, principally globin, in mammalian erythroid cells. We identified two HRI-related kinases from Schizosaccharomyces pombe which have full-length homology with mammalian HRI. The two HRI-related kinases, named Hri1p and Hri2p, exhibit autokinase and kinase activity specific for Ser-51 of eIF2alpha, and both activities were inhibited in vitro by hemin, as previously described for mammalian HRI. Overexpression of Hri1p, Hri2p, or the human eIF2alpha kinase, double-stranded-RNA-dependent protein kinase (PKR), impeded growth of S. pombe due to elevated phosphorylation of eIF2alpha. Cells from strains with deletions of the hri1(+) and hri2(+) genes, individually or in combination, exhibited a reduced growth rate when exposed to heat shock or to arsenic compounds. Measurements of in vivo phosphorylation of eIF2alpha suggest that Hri1p and Hri2p differentially phosphorylate eIF2alpha in response to these stress conditions. These results demonstrate that HRI-related enzymes are not unique to vertebrates and suggest that these eIF2alpha kinases are important participants in diverse stress response pathways in some lower eukaryotes.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhan
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Vattem
authors.forename: Bettina N
authors.initials: BN
authors.lastname: Bauer
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Dever
authors.forename: Jane-Jane
authors.initials: JJ
authors.lastname: Chen
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
mesh_terms: D000595:Amino Acid Sequence; D001149:Arsenates / Q000494:pharmacology; D001483:Base Sequence; D002455:Cell Division; D004271:DNA, Fungal; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism; D013379:Substrate Specificity; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D001149:Arsenates; D004271:DNA, Fungal; D015852:Eukaryotic Initiation Factor-2; D005656:Fungal Proteins; D029702:Schizosaccharomyces pombe Proteins; D012694:Serine; C466820:Hri1p protein, S pombe; C466819:Hri2p protein, S pombe; D019892:eIF-2 Kinase; C025657:arsenic acid