In order to grow, cells must tightly coordinate biosynthetic processes with catabolic programs. The master regulator, mechanistic target of rapamycin complex 1 (mTORC1) kinase, integrates signals from nutrients, hormones and energy to control the balance between cellular growth and repair programs. In a key step, nutrients drive the localization of mTORC1 to the lysosomal membrane, where mTORC1 becomes competent to phosphorylate its downstream targets. Cholesterol was recently identified as a major nutrient input for lysosomal mTORC1 activation. Cholesterol sensing occurs upstream of the heterodimeric Rag GTPases, and involves its active exchange between the limiting membranes of lysosomes and the endoplasmic reticulum. Moreover, this process is negatively regulated by the cholesterol exporter, Niemann-Pick C1 (NPC1) protein, loss of which leads to mTORC1 hyperactivation and to mTORC1-dependent disruption of autophagy and mitochondrial function, implicating dysregulated mTORC1 signaling as a pathogenic driver of Niemann-Pick type C. Despite these advances, our understanding of how cholesterol regulates mTORC1 remains fragmentary. In particular, we lack a complete knowledge of the cholesterol-regulated proteins that translate lysosomal cholesterol levels to modulation of the Rag GTPases. I will present our recent effort to unravel lysosomal cholesterol sensing through a combination of organelle proteomics, bioinformatic analysis and functional assays both in vitro and in cell. This work illuminates the fundamental logic of lysosomal nutrient sensing, and could increase the understanding of Niemann-Pick type C pathogenesis.
THIS SEMINAR WILL BE VIRTUAL ONLY.
Seminar with Roberto Zoncu
University of California Berkeley