The role of Folliculin, tumor suppressor mutated in BHD, in mTOR nutrient sensing

描述(申请人提供)：雷帕霉素复合体1(MTORC1)蛋白激酶的机制靶标是生长的主要调节因子。它集成了一系列不同的信号，包括营养可获得性、能量水平、生长因子和细胞压力，以调节眼部的动态平衡过程，如核糖体生物发生、蛋白质翻译和自噬。不足为奇的是，在癌症、糖尿病和神经变性等常见人类疾病中，这一途径被解除了调控。虽然控制生长因子、能量水平和细胞压力感知的机制已经很好地描述了，但营养感知仍然相对较少被理解。营养物质是激酶活性所必需的，并利用一种独立于其他输入的机制来调节mTORC1途径。阐明控制营养感知的分子机制是开发针对mTORC1途径的更有效的治疗方法的基础，同时将副作用降至最低。我们使用蛋白质组学的方法，确定了在家族性癌症综合征Birt-Hogg-Dube(BHD)中突变的肿瘤抑制因子毛囊蛋白(Flcn)与mTORC1途径的营养感应轴之间的新联系。尽管Flcn与一种人类疾病有关，但其功能仍不清楚。初步证据表明，Fln在氨基酸饥饿时移位到溶酶体，与mTORC1营养反应的关键调节因子Rag GTP酶和Ragator复合体相互作用。本项目的目的是研究Flcn和Flcn相互作用蛋白1和2(FNIPs)在营养感知mTORC1途径中的功能。我们提出了以下目标：1)表征不同营养条件下FLCN与RAGS和Ragator复合体的相互作用和定位。2)确定在不同营养条件下，Flcn/FNIPs基因敲除和过表达对mTORC1活性和定位的影响。3)研究Flcn/FNIPs调控Rag GTP酶和Ragator复合体活性的机制。通过假设驱动和无偏倚的方法，我们提出的工作将阐明肿瘤抑制基因Flcn在人类癌症中常见的mTORC1途径中的功能。这些见解将有助于阐明BHD的发病机制，并可能导致癌症新疗法的合理发展。

DESCRIPTION (provided by applicant): The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master regulator of growth. It integrates a diverse set of signals, including nutrient availability, energy levels, growth factors, and cellular stresses, to regulate ey homeostatic processes such as ribosome biogenesis, protein translation, and autophagy. Not surprisingly, this pathway is deregulated in common human diseases such as cancer, diabetes, and neurodegeneration. While the mechanisms governing the sensing of growth factors, energy levels, and cellular stresses are well characterized, nutrient sensing remains relatively poorly understood. Nutrients are absolutely required for kinase activity and utilize an independent mechanism from other inputs to regulate the mTORC1 pathway. Elucidation of the molecular mechanisms that control nutrient sensing is fundamental for the development of therapies that target the mTORC1 pathway with more efficacy, while minimizing side effects. We have used a proteomic approach to identify a new link between folliculin (FLCN), the tumor suppressor mutated in the familial cancer syndrome Birt-Hogg-Dube (BHD), and the nutrient sensing axis of the mTORC1 pathway. Despite its causative link to a human disease, the function of FLCN remains unclear. Preliminary evidence suggests that FLCN translocates to the lysosome in response to amino acid starvation to interact with the Rag GTPases and the Ragulator complex, key regulators of the mTORC1 nutrient response. The goal of this project is to characterize the functions of FLCN and FLCN interacting protein 1 and 2 (FNIPs) in the nutrient sensing mTORC1 pathway. We propose the following aims: 1) Characterize the FLCN interaction and localization with the Rags and Ragulator complex under different nutrient conditions. 2) Determine the effects of FLCN/FNIPs knockdown and overexpression on mTORC1 activity and localization under different nutrient conditions. 3) Investigate the mechanism through which FLCN/FNIPs modulate the activity of the Rag GTPases and the Ragulator complex. Through hypothesis driven and unbiased approaches, our proposed work will clarify how the tumor suppressor FLCN functions in the mTORC1 pathway commonly deregulated in human cancers. These insights will shed light on the pathogenesis of BHD and may lead to the rational development of novel therapies for cancer.