Wnt5a Belongs to the Lysosomal Cholesterol-Sensing Machinery that Controls mTORC1

The Wnt ligand, Wnt5a limits cellular cholesterol accumulation, however, it role in atherosclerosis is unknown. Here, we show that mice deleted for Wnt5a in vascular smooth muscle cells (VSMCs) developed atherosclerosis lesions when fed a cholesterol-rich diet. VSMCs accumulated cholesterol in enlarged endosome/lysosome (LELs), and lipofuscin containing vesicles. We identified Wnt5a, as a member of the nutrient/energy/stress sensor, mTORC1 scaffolding complex, which drives lysosomal fonction and promotes cholesterol trafficking. By decreasing mTORC1 activity, Wnt5a senses changes in dietary cholesterol supply, promotes LELs cholesterol egress to the endoplasmic reticulum (ER), and protects against atherosclerosis. Moreover, Wnt5a binds cholesterol-rich membranes and interacts with the polytopic membrane-bound Niemann–Pick C1 (NPC1) and soluble Niemann–Pick C2 (NPC2), two lysosomal proteins that regulate cholesterol export from LELs. Consequently, absence of Wnt5a decoupled mTORC1 from variations in LELs sterol levels, and this resulted in accumulation of large intracellular inclusion bodies, large LELs, decreased cholesterol content in the ER, activation of the sterol regulatory element-binding protein-2 (SREBP-2) a master regulator of cholesterol biosynthesis. These results reveal an unexpected function of the Wnt5a pathway, and provide a conceptually new basis for future drug development to prevent cholesterol accumulation, atherosclerosis, and lysosomal storage diseases.