Mechanisms of mTORC1 signaling to protein degradation pathways

雷帕霉素复合物 1 (mTORC1) 的机制目标是发挥营养感应机制 调节细胞生长和代谢的核心作用。 mTORC1 功能的紊乱与 人类疾病，例如癌症、糖尿病、神经退行性疾病以及与年龄相关的病症。尽管 我们对 mTORC1 通路的了解的最新进展，mTORC1 如何协调不同的 下游过程仍然知之甚少。我们最近的研究表明 mTORC1 主动 除了在自噬中的作用之外，还参与调节蛋白质降解。 mTORC1 促进转变 蛋白酶体群体向免疫蛋白酶体（一种诱导型蛋白酶体）转变，这有助于 去除一组选择性的蛋白质。我们还发现 mTORC1 调节血浆降解 膜蛋白，例如 EGF 受体，通过内吞途径。这些发现表明 mTORC1 在细胞蛋白质降解中具有广泛的功能。更好地理解扩展 mTORC1 在蛋白质降解中的作用将对广泛的研究产生重大影响，并将提供 对治疗与 mTORC1 相关的人类疾病的更好治疗策略的新见解 失调。我们未来五年研究计划的目标是确定机制 mTORC1 通过三种不同的途径调节蛋白质降解。首先，我们将定义 mTORC1-ULK1 通路调节自噬诱导、吞噬细胞的机制 成核、自噬膜与溶酶体融合以及溶酶体重组。我们将广泛 研究 mTORC1 和 ULK1 介导的相互作用和磷酸化在调节中的作用 自噬过程。使用尖端的细胞成像技术和基因组编辑工具，我们将 确定内源性成分、招募和定位/共定位的动态变化 吞噬泡和自噬体形成过程中的自噬蛋白。其次，我们将定义 mTORC1 调节内体-溶酶体途径的机制。我们将确定关键 mTORC1 调节的内体因子及其相互作用和磷酸化并决定它们的 细胞表面蛋白内吞降解中的作用。第三，我们要明确各部门的作用。 免疫蛋白酶体介导 mTORC1 信号传导以调节细胞生理和代谢。我们会 识别优先被免疫蛋白酶体消化的蛋白质。我们将确定功能 这些优先降解的重要性，旨在阐明以前未知的机制 细胞对压力和生长信号的反应。通过这些研究方向，我们的研究计划 将增进 mTOR 在协调营养、生长和应激方面的功能的基础知识 膜相关蛋白降解途径和蛋白酶体机制的状态，以及 为与 mTORC1 失调相关的人类疾病的发病机制提供新的见解。

The mechanistic target of rapamycin complex 1 (mTORC1) is the nutrient sensing machinery that plays central roles in regulating cell growth and metabolism. Disturbance of mTORC1 functions is associated with human diseases, such as cancer, diabetes, and neurodegeneration, and age-related pathologies. Despite the recent progress in our knowledge on the mTORC1 pathway, how mTORC1 coordinates diverse downstream processes remains poorly understood. Our recent studies revealed that mTORC1 actively engages in regulating protein degradation beyond its role in autophagy. mTORC1 promotes a shift of proteasome population to the immunoproteasome, an inducible type of proteasome, which facilitates removal of a selective group of proteins. We also found that mTORC1 regulates degradation of plasma membrane proteins, such as EGF receptor, via the endocytic pathway. These findings suggest that mTORC1 has a broad range of functions in cellular protein degradation. Better understanding the expanded roles of mTORC1 in protein degradation will have high impact in a wide range of research and will provide novel insight into better therapeutic strategies to treat human diseases associated with mTORC1 dysregulation. The goal of our research program in the next five years is to determine the mechanisms by which mTORC1 regulates protein degradation via three different pathways. First, we will define the mechanisms through which the mTORC1-ULK1 pathway regulates autophagy induction, phagophore nucleation, autophagic membrane fusion with lysosomes, and lysosome reformation. We will extensively investigate the roles of mTORC1- and ULK1-mediated interactions and phosphorylations in regulation of autophagy processes. Using cutting-edge cell imaging techniques and genome-editing tools, we will determine dynamic changes of composition, recruitment, and localization/colocalization of endogenous autophagy proteins during the formation of phagophore and autophagosome. Second, we will define the mechanisms through which mTORC1 regulates the endosome-lysosomal pathway. We will identify key endosomal factors and their interactions and phosphorylations regulated by mTORC1 and determine their roles in endocytic degradation of cell surface proteins. Third, we will elucidate the roles of the immunoproteasome in mediating mTORC1 signaling to regulate cell physiology and metabolism. We will identify proteins that are preferentially digested by the immunoproteasome. We will determine the functional significance of those preferential degradations, aiming to elucidate previously-unknown mechanisms for cellular response to stress and growth signals. Through these directions of research, our research program will advance the fundamental knowledge on mTOR functions in coordinating nutrient, growth and stress status with the membrane-associated protein degradation pathways and the proteasome machinery, and provide novel insight into the pathogenesis of human diseases associated with mTORC1 dysregulation.