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

描述（由申请人提供）：雷帕霉素复合物1 （mTORC1）蛋白激酶的机制靶点是生长的主要调节剂。它整合了多种信号，包括营养可利用性、能量水平、生长因子和细胞应激，以调节关键的稳态过程，如核糖体生物发生、蛋白质翻译和自噬。不足为奇的是，这种途径在癌症、糖尿病和神经退行性疾病等常见人类疾病中是不受控制的。虽然控制生长因子、能量水平和细胞应激的感知机制已经很好地表征了，但对营养感知的了解仍然相对较少。营养物质是激酶活性所必需的，并且利用一种独立于其他输入的机制来调节mTORC1通路。阐明控制营养感知的分子机制是开发靶向mTORC1途径的治疗方法的基础，这些治疗方法更有效，同时最大限度地减少副作用。我们使用蛋白质组学方法确定了滤泡蛋白（FLCN），家族性癌症综合征Birt-Hogg-Dube （BHD）中突变的肿瘤抑制因子与mTORC1途径的营养传感轴之间的新联系。尽管FLCN与人类疾病有致病关系，但其功能仍不清楚。初步证据表明，FLCN在氨基酸缺乏的情况下易位到溶酶体上，与Rag GTPases和调控复合物相互作用，后者是mTORC1营养反应的关键调控因子。本项目的目的是表征FLCN和FLCN相互作用蛋白1和2 （FNIPs）在营养传感mTORC1通路中的功能。我们提出了以下目标：1)表征在不同营养条件下FLCN与Rags和regulator复合物的相互作用和定位。2)确定不同营养条件下FLCN/FNIPs敲低和过表达对mTORC1活性和定位的影响。3)研究FLCN/FNIPs调控Rag gtp酶和调控复合物活性的机制。通过假设驱动和无偏见的方法，我们提出的工作将阐明肿瘤抑制因子FLCN如何在人类癌症中通常失调的mTORC1通路中起作用。这些见解将阐明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.