感应特定氨基酸信号的新型TORC1调控因子的筛选及机制研究

TORC1是重要的感知营养并调控细胞生长的信号中枢，其失调会导致各种疾病。氨基酸是激活TORC1的关键信号，可通过RAG GTP酶依赖或非依赖的机制调控TORC1活性。RAG依赖的TORC1调控机制已较清楚，但RAG非依赖的TORC1调控机制仍不明确。我们最近从酵母中鉴定出一个新的RAG非依赖并特异性感应低浓度亮氨酸信号的TORC1抑制因子Whi2。其功能在哺乳动物同源蛋白KCTD中保守，可解释因KCTD突变导致的癌症和癫痫（PLoS Genetics，2018）。由于Whi2只能在亮氨酸缺乏条件下被鉴定出，我们猜测还有更多感应特定氨基酸信号的TORC1调控因子尚待发现。本项目将利用TORC1通路在酵母中的高度保守性，在特定氨基酸条件下进行酵母全基因组筛选，探索新的TORC1调控因子和调控机制。这有助于我们理解因TORC1信号通路失调而引起的疾病病理机制，为药物研发提供潜在新靶点。

TORC1 is an important signaling hub that controls cell growth in response to nutrient signals. Its dysregulation can cause various diseases. Amino acids are key signaling molecules that regulate TORC1 activity through RAG GTPase-dependent or independent mechanisms. The RAG-dependent TORC1 regulation mechanism has been thoroughly illustrated, but the RAG-independent TORC1 regulation mechanism remains unclear. We recently uncovered a novel RAG-independent TORC1 inhibitor - Whi2, which specifically senses low leucine signal in yeast. Its ability to inhibit TORC1 is conserved in mammalian KCTD proteins, homologs of Whi2. Such function of KCTD can well explain the cause of certain diseases such as cancer and epilepsy resulted from KCTD mutations. Since Whi2 can only be identified as the inhibitor of TORC1 under low leucine conditions, we hypothesize that more TORC1 regulators sensing specific amino acid signals remain to be discovered. In this project, by taking advantage of the highly conserved TORC1 signaling pathway in yeast, we propose to run high-throughput screens in the genome-wide yeast knockout collection under specific amino acid conditions, to explore novel TORC1 regulators and regulatory mechanisms. The successful implementation of this project will help us understand the pathological mechanisms of diseases caused by dysregulation of the TORC1 signaling pathway, and is likely to provide potential novel targets for drug development.