Hsp90 binds and regulates Gcn2, the ligand-inducible kinase of the alpha subunit of eukaryotic translation initiation factor 2 [corrected].
The protein kinase Gcn2 stimulates translation of the yeast transcription factor Gcn4 upon amino acid starvation. Using genetic and biochemical approaches, we show that Gcn2 is regulated by the molecular chaperone Hsp90 in budding yeast Saccharomyces cerevisiae. Specifically, we found that (i) several Hsp90 mutant strains exhibit constitutive expression of a GCN4-lacZ reporter plasmid; (ii) Gcn2 and Hsp90 form a complex in vitro as well as in vivo; (iii) the specific inhibitors of Hsp90, geldanamycin and macbecin I, enhance the association of Gcn2 with Hsp90 and inhibit its kinase activity in vitro; (iv) in vivo, macbecin I strongly reduces the levels of Gcn2; (v) in a strain expressing the temperature-sensitive Hsp90 mutant G170D, both the accumulation and activity of Gcn2 are abolished at the restrictive temperature; and (vi) the Hsp90 cochaperones Cdc37, Sti1, and Sba1 are required for the response to amino acid starvation. Taken together, these data identify Gcn2 as a novel target for Hsp90, which plays a crucial role for the maturation and regulation of Gcn2.
Donzé
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Département de Biologie Cellulaire, Université de Genève, Sciences III, CH-1211 Geneva 4, Switzerland.
Picard
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D020121:5' Untranslated Regions; D016227:Benzoquinones; D018797:Cell Cycle Proteins / Q000378:metabolism; D018833:Chaperonins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007763:Lac Operon; D047029:Lactams, Macrocyclic; D008024:Ligands; D018832:Molecular Chaperones / Q000378:metabolism; D016296:Mutagenesis; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011809:Quinones; D012333:RNA, Messenger; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins
D020121:5' Untranslated Regions; D016227:Benzoquinones; C513270:CDC37 protein, S cerevisiae; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005656:Fungal Proteins; C074510:HSP82 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; D018832:Molecular Chaperones; D010448:Peptide Initiation Factors; D011809:Quinones; D012333:RNA, Messenger; C113025:SBA1 protein, S cerevisiae; C542289:STI1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C025514:macbecin I; D011494:Protein Kinases; D018833:Chaperonins; C001277:geldanamycin