Mammalian eukaryotic initiation factor 2α kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast

Thomas E. Dever, Jane Jane Chen, Glen N Barber, A. Mark Cigan, Lan Feng, Thomas F. Donahue, Irving M. London, Michael G. Katze, Alan G. Hinnebusch

Research output: Contribution to journalArticle

175 Citations (Scopus)

Abstract

Phosphorylation of the αsubunit of eukaryotic initiation factor 2 (eIF-2α) in Saccharomyces cerevisiae by the GCN2 protein kinase stimulates the translation of GCN4 mRNA. The protein kinases heme-regulated inhibitor of translation (HRI) and double-stranded RNA-dependent eIF-2α protein kinase (dsRNA-PK) inhibit initiation of translation in mammalian cells by phosphorylating Ser-51 of eIF-2α. We show that HRI and dsRNA-PK phosphorylate yeast eIF-2α in vitro and in vivo and functionally substitute for GCN2 protein to stimulate GCN4 translation in yeast. In addition, high-level expression of either mammalian kinase in yeast decreases the growth rate, a finding analogous to the inhibition of total protein synthesis by these kinases in mammalian cells. Phosphorylation of eIF-2α inhibits initiation in mammalian cells by sequestering eIF-2B, the factor required for exchange of GTP for GDP on eIF-2. Mutations in the GCN3 gene, encoding a subunit of the yeast eIF-2B complex, eliminate the effects of HRI and dsRNA-PK on global and GCN4-specific translation in yeast. These results provide further in vivo evidence that phosphorylation of eIF-2α inhibits translation by impairing eIF-2B function and identify GCN3 as a regulatory subunit of eIF-2B. These results also suggest that GCN4 translational control will be a good model system to study how mammalian eIF-2α kinases are modulated by environmental signals and viral regulatory factors.

Original languageEnglish
Pages (from-to)4616-4620
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number10
StatePublished - May 15 1993
Externally publishedYes

Fingerprint

Eukaryotic Initiation Factor-2
Protein Kinases
Phosphotransferases
Yeasts
Double-Stranded RNA
Heme
eIF-2 Kinase
Phosphorylation
Saccharomyces cerevisiae Proteins
Protein Biosynthesis
Guanosine Triphosphate
Mutation

Keywords

  • Double-stranded RNA-dependent eIF-2α kinase
  • Heme-regulated eukaryotic initiation factor 2α kinase
  • Initiation factors
  • p68 kinase
  • Phosphorylation

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

Mammalian eukaryotic initiation factor 2α kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast. / Dever, Thomas E.; Chen, Jane Jane; Barber, Glen N; Cigan, A. Mark; Feng, Lan; Donahue, Thomas F.; London, Irving M.; Katze, Michael G.; Hinnebusch, Alan G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 90, No. 10, 15.05.1993, p. 4616-4620.

Research output: Contribution to journalArticle

Dever, Thomas E. ; Chen, Jane Jane ; Barber, Glen N ; Cigan, A. Mark ; Feng, Lan ; Donahue, Thomas F. ; London, Irving M. ; Katze, Michael G. ; Hinnebusch, Alan G. / Mammalian eukaryotic initiation factor 2α kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast. In: Proceedings of the National Academy of Sciences of the United States of America. 1993 ; Vol. 90, No. 10. pp. 4616-4620.
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