Division of Molecular Pharmacology and Pharmacogenomics, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
Genetics. 2013 Oct;195(2):457-68. doi: 10.1534/genetics.113.154674. Epub 2013 Aug 9.
The target of rapamycin (TOR) is a highly conserved protein kinase that regulates cell growth and metabolism. Here we performed a genome-wide screen to identify negative regulators of TOR complex 1 (TORC1) in Schizosaccharomyces pombe by isolating mutants that phenocopy Δtsc2, in which TORC1 signaling is known to be up-regulated. We discovered that Δnpr2 displayed similar phenotypes to Δtsc2 in terms of amino acid uptake defects and mislocalization of the Cat1 permease. However, Δnpr2 and Δtsc2 clearly showed different phenotypes in terms of rapamycin supersensitivity and Isp5 transcription upon various treatments. Furthermore, we showed that Tor2 controls amino acid homeostasis at the transcriptional and post-transcriptional levels. Our data reveal that both Npr2 and Tsc2 negatively regulate TORC1 signaling, and Npr2, but not Tsc2, may be involved in the feedback loop of a nutrient-sensing pathway.
雷帕霉素靶蛋白（TOR）是一种高度保守的蛋白激酶，可调节细胞生长和代谢。在这里，我们通过分离出模拟Δtsc2 的突变体，对裂殖酵母中的 TOR 复合物 1（TORC1）的负调控因子进行了全基因组筛选，已知 TORC1 信号转导在Δtsc2 中被上调。我们发现，Δnpr2 在氨基酸摄取缺陷和 Cat1 通透酶的定位错误方面与Δtsc2 表现出相似的表型。然而，Δnpr2 和 Δtsc2 在不同处理下雷帕霉素超敏性和 Isp5 转录方面表现出明显不同的表型。此外，我们表明 Tor2 在转录和转录后水平控制氨基酸的动态平衡。我们的数据表明，Npr2 和 Tsc2 均负调控 TORC1 信号，而 Npr2 （而非 Tsc2）可能参与了营养感应途径的反馈回路。
