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

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作者：

TE Dever，JJ Chen，GN Barber，AM Cigan，L Feng，TF Donahue，IM London，MG Katze，AG Hinnebusch

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摘要：

Phosphorylation of the α subunit 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.

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关键词：

Biochemistry Phosphorylation Initiation Factors Double-Stranded RNA-Dependent eIF-2α Kinase p68 Kinase Heme-Regulated Eukaryotic Initiation Factor 2α Kinase

DOI：

10.1073/pnas.90.10.4616

被引量：

562

年份：

1993