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

T. E. Dever, J. J. Chen, G. N. Barber, A. M. Cigan, L. Feng, T. F. Donahue, I. M. London, M. G. Katze, A. G. Hinnebusch

Research output: Contribution to journalArticle

180 Scopus citations

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 (US)
Pages (from-to)4616-4620
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number10
DOIs
StatePublished - Jan 1 1993
Externally publishedYes

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

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