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PMID: 12242291 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Phosphorylation of eukaryotic initiation factor 2 by heme-regulated inhibitor kinase-related protein kinases in Schizosaccharomyces pombe is important for fesistance to environmental stresses.

Molecular and cellular biology ·Vol. 22 ·No. 20 ·2002-10-00 ·Pages 7134-46

Zhan K, Vattem KM, Bauer BN, Dever TE, Chen JJ, Wek RC

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.

MeSH Terms
Amino Acid Sequence Arsenates/pharmacology Base Sequence Cell Division DNA, Fungal Eukaryotic Initiation Factor-2/metabolism Fungal Proteins/genetics,metabolism Heat-Shock Response Humans Molecular Sequence Data Phosphorylation Schizosaccharomyces/drug effects,genetics,metabolism Schizosaccharomyces pombe Proteins/genetics,metabolism Sequence Homology, Amino Acid Serine/metabolism Substrate Specificity eIF-2 Kinase/genetics,metabolism
Chemicals
Arsenates DNA, Fungal Eukaryotic Initiation Factor-2 Fungal Proteins Schizosaccharomyces pombe Proteins Serine Hri1p protein, S pombe Hri2p protein, S pombe eIF-2 Kinase arsenic acid
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Zhan Ke
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Vattem Krishna M
Bauer Bettina N
Dever Thomas E
Chen Jane-Jane
Wek Ronald C
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.22.20.7134-7146.2002
Published
2002-10-00
Pages
7134-46
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC139816
Subset
IM
Grants
NIGMS NIH HHS · R01GM49164 · United States
NIDDK NIH HHS · R01 DK016272 · United States
NIGMS NIH HHS · R01 GM049164 · United States
NIDDK NIH HHS · R01DK53223 · United States
NIGMS NIH HHS · R01GM643540 · United States
Databases
GENBANK
AF536223, AF536224
External Links
PubMed source DOI: 10.1128/MCB.22.20.7134-7146.2002 PMC Full Text View journal details
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