title: Retrograde response to mitochondrial dysfunction is separable from TOR1/2 regulation of retrograde gene expression.
abstract: Retrograde (RTG) signaling senses mitochondrial dysfunction and initiates readjustments of carbohydrate and nitrogen metabolism through nuclear accumulation of the heterodimeric transcription factors, Rtg1/3p. The RTG pathway is also linked to target of rapamycin (TOR) signaling, among whose activities is transcriptional control of nitrogen catabolite repression (NCR)-sensitive genes. To investigate the connections between these two signaling pathways, we have analyzed rapamycin sensitivity of the expression of the RTG target gene CIT2 and of two NCR-sensitive genes, GLN1 and DAL5, in respiratory-competent (rho+) and -incompetent (rho0) yeast cells. Here we have presented evidence that retrograde gene expression is separable from TOR regulation of RTG- and NCR-responsive genes. We showed that expression of these two classes of genes is differentially regulated by glutamate starvation whether in response to mitochondrial dysfunction or induced by rapamycin treatment, as well by glutamine or histidine starvation. We also showed that Lst8p, a component of the TOR1/2 complexes and a negative regulator of the RTG pathway, has multiple roles in the regulation of RTG- and NCR-sensitive genes. Lst8p negatively regulates CIT2 and GLN1 expression, whereas DAL5 expression is independent of Lst8p function. DAL5 expression depends on the GATA transcription factors Gln3p and Gat1p. Gat1p is translocated to the nucleus only upon TOR inhibition by rapamycin. Altogether, these data show that Rtg1/3p, Gln3p, and Gat1p can be differentially regulated through different nutrient-sensing pathways, such as TOR and retrograde signaling, and by multiple factors, such as Lst8p, which is suggested to have a role in connecting the RTG and TOR pathways.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Giannattasio
authors.forename: Zhengchang
authors.initials: Z
authors.lastname: Liu
authors.forename: Janet
authors.initials: J
authors.lastname: Thornton
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Butow
mesh_terms: D000483:Alleles; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology*; D015152:Blotting, Northern; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002467:Cell Nucleus / Q000378:metabolism; D019281:Dimerization; D015966:Gene Expression Regulation, Fungal; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D005973:Glutamine / Q000737:chemistry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000473:pathology*; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009584:Nitrogen / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis*; D010957:Plasmids / Q000378:metabolism; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D005974:Glutamate-Ammonia Ligase; D005971:Glutamates; D005973:Glutamine; D049452:Green Fluorescent Proteins; D006639:Histidine; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D009584:Nitrogen; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D029701:Saccharomyces cerevisiae Proteins; C503299:DAL5 protein, S cerevisiae; C110280:LST8 protein, S cerevisiae; C079378:RTG1 protein, S cerevisiae; C104438:RTG3 protein, S cerevisiae; C083324:TOR1 protein, S cerevisiae; C081135:TOR2 protein, S cerevisiae