Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; The Paul F. Glenn Center for Aging Research at the University of California, Berkeley, Berkeley, CA 94720, USA.
Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Department of Pediatric Gastroenterology, Hepatology, and Nutrition, University of California, San Diego, La Jolla, CA 92037, USA.
Dev Cell. 2021 Feb 8;56(3):260-276.e7. doi: 10.1016/j.devcel.2020.11.016. Epub 2020 Dec 11.
Lysosomes promote cellular homeostasis through macromolecular hydrolysis within their lumen and metabolic signaling by the mTORC1 kinase on their limiting membranes. Both hydrolytic and signaling functions require precise regulation of lysosomal cholesterol content. In Niemann-Pick type C (NPC), loss of the cholesterol exporter, NPC1, causes cholesterol accumulation within lysosomes, leading to mTORC1 hyperactivation, disrupted mitochondrial function, and neurodegeneration. The compositional and functional alterations in NPC lysosomes and nature of aberrant cholesterol-mTORC1 signaling contribution to organelle pathogenesis are not understood. Through proteomic profiling of NPC lysosomes, we find pronounced proteolytic impairment compounded with hydrolase depletion, enhanced membrane damage, and defective mitophagy. Genetic and pharmacologic mTORC1 inhibition restores lysosomal proteolysis without correcting cholesterol storage, implicating aberrant mTORC1 as a pathogenic driver downstream of cholesterol accumulation. Consistently, mTORC1 inhibition ameliorates mitochondrial dysfunction in a neuronal model of NPC. Thus, cholesterol-mTORC1 signaling controls organelle homeostasis and is a targetable pathway in NPC.
溶酶体通过腔内大分子水解以及其限膜上的 mTORC1 激酶进行代谢信号传递，从而促进细胞内稳态。水解和信号传递功能都需要溶酶体胆固醇含量的精确调节。在尼曼-匹克 C 型（NPC）中，胆固醇外排蛋白 NPC1 的缺失导致溶酶体内胆固醇积累，从而导致 mTORC1 过度激活、线粒体功能障碍和神经退行性变。NPC 溶酶体的组成和功能改变以及异常胆固醇-mTORC1 信号传递对细胞器发病机制的性质尚不清楚。通过 NPC 溶酶体的蛋白质组学分析，我们发现明显的蛋白水解损伤伴随着水解酶耗竭、增强的膜损伤和有缺陷的线粒体自噬。遗传和药理学 mTORC1 抑制恢复溶酶体蛋白水解而不纠正胆固醇储存，表明异常的 mTORC1 作为胆固醇积累下游的致病驱动因素。一致地，mTORC1 抑制改善 NPC 神经元模型中的线粒体功能障碍。因此，胆固醇-mTORC1 信号控制细胞器内稳态，是 NPC 的一个可靶向途径。
