Lysosome-peroxisome Membrane Contacts Mediate Cholesterol Transport

Abstract: Cholesterol is an essential lipid for eukaryotic cells. Its major function is regulating membrane characters. Cholesterol is not evenly distributed among different organelles and is dynamically transported in the cell. However， the mechanism underlying intracellular cholesterol transport has remained largely unknown. We established an amphotericin B-based assay enabling a genome-wide shRNA screen for delayed LDL-cholesterol transport， and identified 341 hits with particular enrichment of peroxisome genes， suggesting a previously unappreciated pathway for cholesterol transport. We showed dynamic membrane contact between peroxisome and lysosome， which was mediated by lysosomal Synaptotagmin VII binding to the lipid PI(4，5)P2 on peroxisomal membrane. LDL-cholesterol enhances such contact and cholesterol is transported from lysosome to peroxisome. Disruption of critical peroxisome genes leads to cholesterol accumulation in lysosome. Together， these findings reveal an unexpected role of peroxisome in intracellular cholesterol transport. We further demonstrate massive cholesterol accumulation in human patient cells and mouse model of peroxisomal disorders， suggesting a contribution of abnormal cholesterol accumulation to the diseases.

CSTR: 32200.14.cjcb.2015.06.0001