title: A novel role for protein kinase Gcn2 in yeast tolerance to intracellular acid stress.
abstract: Intracellular pH conditions many cellular systems, but its mechanisms of regulation and perception are mostly unknown. We have identified two yeast genes important for tolerance to intracellular acidification caused by weak permeable acids. One corresponded to LEU2 and functions by removing the dependency of the leu2 mutant host strain on uptake of extracellular leucine. Leucine transport is inhibited by intracellular acidification, and either leucine oversupplementation or overexpression of the transporter gene BAP2 improved acid growth. Another acid-tolerance gene is GCN2, encoding a protein kinase activated by uncharged tRNAs during amino acid starvation. Gcn2 phosphorylates eIF2α (eukaryotic initiation factor 2α) (Sui2) at Ser51 and this inhibits general translation, but activates that of Gcn4, a transcription factor for amino acid biosynthetic genes. Intracellular acidification activates Gcn2 probably by inhibition of aminoacyl-tRNA synthetases because we observed accumulation of uncharged tRNAleu without leucine depletion. Gcn2 is required for leucine transport and a gcn2-null mutant is sensitive to acid stress if auxotrophic for leucine. Gcn4 is required for neither leucine transport nor acid tolerance, but a S51A sui2 mutant is acid-sensitive. This suggests that Gcn2, by phosphorylating eIF2α, may activate translation of an unknown regulator of amino acid transporters different from Gcn4.
authors.affiliation: Instituto de Biología Molecular y Celular de Plantas, Universidad Politécnica de Valencia-CSIC, Camino de Vera s/n, 46022 Valencia, Spain.
authors.forename: Guillem
authors.initials: G
authors.lastname: Hueso
authors.forename: Rafael
authors.initials: R
authors.lastname: Aparicio-Sanchis
authors.forename: Consuelo
authors.initials: C
authors.lastname: Montesinos
authors.forename: Silvia
authors.initials: S
authors.lastname: Lorenz
authors.forename: José R
authors.initials: JR
authors.lastname: Murguía
authors.forename: Ramón
authors.initials: R
authors.lastname: Serrano
mesh_terms: D019342:Acetic Acid; D000222:Adaptation, Physiological; D000596:Amino Acids / Q000378:metabolism; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D007930:Leucine / Q000378:metabolism; D009154:Mutation; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D000596:Amino Acids; D012331:RNA, Fungal; D029701:Saccharomyces cerevisiae Proteins; D012343:RNA, Transfer; C512912:GCN2 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D000604:Amino Acyl-tRNA Synthetases; D007930:Leucine; D019342:Acetic Acid