Mammalian eukaryotic initiation factor 2 alpha kinases functionally substitute for GCN2 protein kinase in the GCN4 translational control mechanism of yeast.
Proceedings of the National Academy of Sciences, 1993•National Acad Sciences
Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha) 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-2 alpha protein kinase (dsRNA-PK) inhibit initiation of
translation in mammalian cells by phosphorylating Ser-51 of eIF-2 alpha. We show that HRI
and dsRNA-PK phosphorylate yeast eIF-2 alpha in vitro and in vivo and functionally …
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-2 alpha protein kinase (dsRNA-PK) inhibit initiation of
translation in mammalian cells by phosphorylating Ser-51 of eIF-2 alpha. We show that HRI
and dsRNA-PK phosphorylate yeast eIF-2 alpha in vitro and in vivo and functionally …
Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha) 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-2 alpha protein kinase (dsRNA-PK) inhibit initiation of translation in mammalian cells by phosphorylating Ser-51 of eIF-2 alpha. We show that HRI and dsRNA-PK phosphorylate yeast eIF-2 alpha 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-2 alpha 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-2 alpha 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-2 alpha kinases are modulated by environmental signals and viral regulatory factors.
National Acad Sciences