title: TORC1 Regulates Developmental Responses to Nitrogen Stress via Regulation of the GATA Transcription Factor Gaf1.
abstract: The TOR (target of rapamycin [sirolimus]) is a universally conserved kinase that couples nutrient availability to cell growth. TOR complex 1 (TORC1) in Schizosaccharomyces pombe positively regulates growth in response to nitrogen availability while suppressing cellular responses to nitrogen stress. Here we report the identification of the GATA transcription factor Gaf1 as a positive regulator of the nitrogen stress-induced gene isp7(+), via three canonical GATA motifs. We show that under nitrogen-rich conditions, TORC1 positively regulates the phosphorylation and cytoplasmic retention of Gaf1 via the PP2A-like phosphatase Ppe1. Under nitrogen stress conditions when TORC1 is inactivated, Gaf1 becomes dephosphorylated and enters the nucleus. Gaf1 was recently shown to negatively regulate the transcription induction of ste11(+), a major regulator of sexual development. Our findings support a model of a two-faceted role of Gaf1 during nitrogen stress. Gaf1 positively regulates genes that are induced early in the response to nitrogen stress, while inhibiting later responses, such as sexual development. Taking these results together, we identify Gaf1 as a novel target for TORC1 signaling and a step-like mechanism to modulate the nitrogen stress response.
  
  
  OBJECTIVE
  TOR complex 1 (TORC1) is an evolutionary conserved protein complex that positively regulates growth and proliferation, while inhibiting starvation responses. In fission yeast, the activity of TORC1 is downregulated in response to nitrogen starvation, and cells reprogram their transcriptional profile and prepare for sexual development. We identify Gaf1, a GATA-like transcription factor that regulates transcription and sexual development in response to starvation, as a downstream target for TORC1 signaling. Under nitrogen-rich conditions, TORC1 positively regulates the phosphorylation and cytoplasmic retention of Gaf1 via the PP2A-like phosphatase Ppe1. Under nitrogen stress conditions when TORC1 is inactivated, Gaf1 becomes dephosphorylated and enters the nucleus. Budding yeast TORC1 regulates GATA transcription factors via the phosphatase Sit4, a structural homologue of Ppe1. Thus, the TORC1-GATA transcription module appears to be conserved in evolution and may also be found in higher eukaryotes.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dana
authors.initials: D
authors.lastname: Laor
authors.affiliation: Department of Natural and Life Sciences, The Open University of Israel, Raanana, Israel.
authors.forename: Adiel
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Martin
authors.initials: M
authors.lastname: Kupiec
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel Department of Natural and Life Sciences, The Open University of Israel, Raanana, Israel ronitt@post.tau.ac.il.
authors.forename: Ronit
authors.initials: R
authors.lastname: Weisman
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D009584:Nitrogen / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D012568:Schizosaccharomyces / Q000235:genetics* / Q000254:growth & development* / Q000502:physiology; D029702:Schizosaccharomyces pombe Proteins / Q000096:biosynthesis / Q000378:metabolism*; D013312:Stress, Physiological; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C114485:Gaf1 protein, S pombe; D046912:Multiprotein Complexes; D029702:Schizosaccharomyces pombe Proteins; D015534:Trans-Activators; C090610:isp7 protein, S pombe; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C106081:ppe1 protein, S pombe; D010749:Phosphoprotein Phosphatases; D009584:Nitrogen