Laor Dana, Cohen Adiel, Kupiec Martin, Weisman Ronit
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.
mBio. 2015 Jul 7;6(4):e00959. doi: 10.1128/mBio.00959-15.
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.
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.
雷帕霉素靶蛋白（TOR，即西罗莫司靶蛋白）是一种普遍保守的激酶，它将营养物质的可利用性与细胞生长联系起来。粟酒裂殖酵母中的TOR复合物1（TORC1）在响应氮可利用性时正向调节生长，同时抑制细胞对氮胁迫的反应。在此，我们报告通过三个典型的GATA基序鉴定出GATA转录因子Gaf1是氮胁迫诱导基因isp7(+)的正向调节因子。我们表明，在富氮条件下，TORC1通过类PP2A磷酸酶Ppe1正向调节Gaf1的磷酸化和细胞质滞留。在氮胁迫条件下，当TORC1失活时，Gaf1去磷酸化并进入细胞核。最近研究表明，Gaf1负向调节性发育的主要调节因子ste11(+)的转录诱导。我们的研究结果支持了Gaf1在氮胁迫期间具有双重作用的模型。Gaf1正向调节在响应氮胁迫早期诱导的基因，同时抑制后期反应，如性发育。综合这些结果，我们确定Gaf1是TORC1信号传导的新靶点以及调节氮胁迫反应的阶梯状机制。
TOR复合物1（TORC1）是一种进化保守的蛋白质复合物，它正向调节生长和增殖，同时抑制饥饿反应。在裂殖酵母中，TORC1的活性在响应氮饥饿时下调，细胞重新编程其转录谱并为性发育做准备。我们鉴定出Gaf1，一种响应饥饿调节转录和性发育的GATA样转录因子，作为TORC1信号传导的下游靶点。在富氮条件下，TORC1通过类PP2A磷酸酶Ppe1正向调节Gaf1的磷酸化和细胞质滞留。在氮胁迫条件下，当TORC1失活时，Gaf1去磷酸化并进入细胞核。芽殖酵母TORC1通过磷酸酶Sit4调节GATA转录因子，Sit4是Ppe1的结构同源物。因此，TORC1 - GATA转录模块在进化中似乎是保守的，并且可能也存在于高等真核生物中。
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