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Mechanisms of mTORC1 signaling to protein degradation pathways

mTORC1 信号传导至蛋白质降解途径的机制

基本信息

批准号：
10796367
负责人：
Do-Hyung Kim
金额：
$ 25万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-08 至 2025-02-28
项目状态：
未结题

项目摘要

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.

雷帕霉素复合体1 （mTORC1）的机制靶点是起作用的营养传感机制

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ULK1 forms distinct oligomeric states and nanoscopic structures during autophagy initiation.

ULK1在自噬开始过程中形成不同的低聚物状态和纳米镜结构。

DOI：
10.1126/sciadv.adh4094
发表时间：
2023-09-29
期刊：
SCIENCE ADVANCES
影响因子：
13.6
作者：
Banerjee, Chiranjib;Mehra, Dushyant;Song, Daihyun;Mancebo, Angel;Park, Ji-Man;Kim, Do-Hyung;Puchner, Elias M.
通讯作者：
Puchner, Elias M.

A paradigm shift: AMPK negatively regulates ULK1 activity.

范式转变：AMPK 负向调节 ULK1 活性。