Molecular Mechanisms of Organelle-based Metabolic Signaling

摘要

ABSTRACT The molecular mechanisms through which cells sense nutrients remain largely unknown, but their elucidation is key to our understanding of metabolic regulation both in normal and disease states. At the center of nutrient sensing and growth regulation is an ancient protein kinase known as the mechanistic Target of Rapamycin Complex 1 (mTORC1). In response to the combined action of metabolic inputs such as nutrients, growth factors, energy and oxygen, mTORC1 translocates from the cytoplasm to the surface of lysosomes, where it becomes activated. Accumulating evidence indicates that aberrant mTORC1 activation at the lysosome could be a driving force in diseases ranging from cancer to type-2 diabetes to neurodegeneration. Thus, a deep mechanistic understanding of how mTORC1 is activated and then inactivated in response to nutrients could point the way to novel therapeutic strategies in these diseases. My lab has made important contributions to the understanding of mTORC1 pathway organization, and how its function is integrated with the many activities of the lysosome. In particular, we have identified a dedicated signaling pathway via which cholesterol, an important building block for cellular membranes, promotes mTORC1 recruitment to the lysosome and activation of its downstream programs. We have uncovered membrane contact sites between lysosomes and the endoplasmic reticulum as key nodes where mTORC1 activation by cholesterol occurs, thus implicating inter-organelle communication as an important aspect of mTORC1 regulation. Furthermore, we found that excess mTORC1 signaling, caused by cholesterol accumulation in the lysosome, drives cellular dysfunction and could be a driving force in a neurodegenerative and metabolic disease, Niemann-Pick type C (NPC). These discoveries directly lead to deep questions on the organization of cellular nutrient sensing, which are at the core of the current MIRA proposal. One key challenge is to elucidate the mechanisms and physiological roles of lipid-dependent mTORC1 regulation, specifically whether dedicated cholesterol sensors exist in the lysosomal membrane, and how they couple the abundance of sterol molecules to mTORC1 activation and to overall metabolic regulation at the cell and organism level. Based on our finding that cholesterol sensing by mTORC1 involves physical communication between the lysosome and the ER, another major goal of the proposal is to delineate the machinery that mediates communication and metabolite exchange between the lysosome and the ER, and how this machinery participates in regulation of mTORC1 as well as another major metabolic kinase, protein kinase A. Finally, the pathogenic role of dysregulated mTORC1 in NPC, and the ability of mTORC1 inhibition to restore several parameters of NPC cell function, strongly support mTORC1 as a prime target in neurodegenerative disease. We will thus determine how lysosomal mTORC1 controls neuronal cell homeostasis, and how dysregulated mTORC1 signaling contributes to neuronal degeneration. Together, these studies will shed light on fundamental principles of metabolic organization in health and disease states.