A novel mechanism for the control of translation initiation by amino acids, mediated by phosphorylation of eukaryotic initiation factor 2B.
Eukaryotic initiation factor 2B (eIF2B) plays a key role in controlling the initiation of mRNA translation. eIF2B is heteropentamer whose catalytic (epsilon) subunit promotes GDP/GTP exchange on eIF2. We show here that depriving human cells of amino acids rapidly results in the inhibition of eIF2B, independently of changes in eIF2 phosphorylation. Although amino acid deprivation also inhibits signaling through the mammalian target of rapamycin complex 1 (mTORC1), the inhibition of eIF2B activity by amino acid starvation is independent of mTORC1. Instead, amino acids repress the phosphorylation of a novel site in eIF2Bepsilon. We identify this site as Ser525, located adjacent to the known phosphoregulatory region in eIF2Bepsilon. Mutation of Ser525 to Ala abolishes the regulation of eIF2B and protein synthesis by amino acids. This indicates that phosphorylation of this site is crucial for the control of eIF2B and protein synthesis by amino acids. These findings identify a new way in which amino acids regulate a key step in translation initiation and indicate that this involves a novel amino acid-sensitive signaling mechanism.
Wang
Xuemin
X
Department of Biochemistry and Molecular Biology, University of British Columbia, Life Sciences Centre, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
Proud
Christopher G
CG
D000409:Alanine / Q000378:metabolism; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D020134:Catalytic Domain; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004622:Embryo, Mammalian; D020717:Eukaryotic Initiation Factor-2B / Q000032:analysis / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D017930:Genes, Reporter; D006639:Histidine / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D007668:Kidney / Q000166:cytology; D008113:Liver Neoplasms / Q000473:pathology; D049410:Luciferases, Renilla / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010449:Peptide Mapping; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
D000596:Amino Acids; D020717:Eukaryotic Initiation Factor-2B; D011500:Protein Synthesis Inhibitors; D012694:Serine; D006639:Histidine; D003513:Cycloheximide; D049410:Luciferases, Renilla; D000409:Alanine