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Triazoles inhibit cholesterol export from lysosomes by binding to NPC1

2016; National Academy of Sciences; Volume: 114; Issue: 1 Linguagem: Inglês

10.1073/pnas.1619571114

1091-6490

Michael N. Trinh, Feiran Lu, Xiaochun Li, Akash Das, Qiren Liang, Jef K. De Brabander, Michael S. Brown, Joseph L. Goldstein,

Cellular transport and secretion

Significance In animal cells, cholesterol is essential for the assembly of membranes and production of steroid hormones and bile acids. Cells obtain cholesterol through receptor-mediated endocytosis of LDL into lysosomes. After lysosomal degradation, LDL-derived cholesterol must cross the lysosomal membrane to execute its functions. Lysosomal export is mediated by Niemann–Pick C1 (NPC1), a membrane protein. Here we show that the triazole drugs posaconazole and itraconazole inhibit lysosomal cholesterol export. A photoactivatable derivative of posaconazole cross-links to NPC1 in intact cells and to purified NPC1 in lipid nanodiscs. A point mutation in the membrane domain of NPC1 prevents lysosomal export of cholesterol and blocks posaconazole cross-linking.