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Molecular and Cellular Biology, October 2002, p. 7134-7146, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.7134-7146.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Eukaryotic Initiation Factor 2 by Heme-Regulated Inhibitor Kinase-Related Protein Kinases in Schizosaccharomyces pombe Is Important for Resistance to Environmental Stresses

Ke Zhan,1 Krishna M. Vattem,1 Bettina N. Bauer,2 Thomas E. Dever,3 Jane-Jane Chen,2 and Ronald C. Wek1*

Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202,1 Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,2 Laboratory of Gene Regulation and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 208923

Received 13 May 2002/ Returned for modification 18 June 2002/ Accepted 19 July 2002

Protein synthesis is regulated by the phosphorylation of the {alpha} subunit of eukaryotic initiation factor 2 (eIF2{alpha}) in response to different environmental stresses. One member of the eIF2{alpha} 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 eIF2{alpha}, and both activities were inhibited in vitro by hemin, as previously described for mammalian HRI. Overexpression of Hri1p, Hri2p, or the human eIF2{alpha} kinase, double-stranded-RNA-dependent protein kinase (PKR), impeded growth of S. pombe due to elevated phosphorylation of eIF2{alpha}. 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 eIF2{alpha} suggest that Hri1p and Hri2p differentially phosphorylate eIF2{alpha} in response to these stress conditions. These results demonstrate that HRI-related enzymes are not unique to vertebrates and suggest that these eIF2{alpha} kinases are important participants in diverse stress response pathways in some lower eukaryotes.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202. Phone: (317) 274-0549. Fax: (317) 274-4686. E-mail: rwek{at}iupui.edu.

Molecular and Cellular Biology, October 2002, p. 7134-7146, Vol. 22, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.20.7134-7146.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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