CAV1 (caveolin 1, caveolae protein, 22kDa) is well known as a principal scaffolding protein of caveolae, a specialized plasma membrane structure. Relatively, the caveolae-independent function of CAV1 is less studied. Autophagy is a process known to involve various membrane structures, including autophagosomes, lysosomes, and autolysosomes for degradation of intracellular proteins and organelles. Currently, the function of CAV1 in autophagy remains largely elusive. In this study, we demonstrate for the first time that CAV1 deficiency promotes both basal and inducible autophagy. Interestingly, the promoting effect was found mainly in the late stage of autophagy via enhancing lysosomal function and autophagosome-lysosome fusion. Notably, the regulatory function of CAV1 in lysosome and autophagy was found to be caveolae-independent, and acts through lipid rafts. Furthermore, the elevated autophagy level induced by CAV1 deficiency serves as a cell survival mechanism under starvation. Importantly, downregulation of CAV1 and enhanced autophagy level were observed in human breast cancer cells and tissues. Taken together, our data reveal a novel function of CAV1 and lipid rafts in breast cancer development via modulation of lysosomal function and autophagy.
Keywords: ATP6V0D1, ATPase H+ transporting lysosomal 38kDa, V0 subunit d1; Baf, bafilomycin A1; CAV1, caveolin 1; CHO, water-soluble cholesterol; CQ, choloroquine; CTSL, cathepsin L; CTxB, cholera toxin subunit B; DRF, detergent-resistant fraction; DSF, detergent-soluble fraction; EGF, epidermal growth factor; KO, knockout; LAMP1, lysosomal-associated membrane protein 1; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MBCD, methyl-β-cyclodextrin; MEF, mouse embryonic fibroblasts; MTOR, mechanistic target of rapamycin; PBS, phosphate-buffered saline; PI, propidium iodide; PLA, proximity ligation assay; PTRF, polymerase I and transcript release factor; TFRC, transferrin receptor; TSC, tuberous sclerosis complex; WT, wild type.; autophagy; breast cancer; caveolin 1; lipid rafts; lysosome; tfLC3B, mRFP-GFP tandem fluorescent-tagged LC3B.