1. Lysosomal regulation of cholesterol homeostasis in tuberous sclerosis complex is mediated via NPC1 and LDL-R.
- Author
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Filippakis H, Alesi N, Ogorek B, Nijmeh J, Khabibullin D, Gutierrez C, Valvezan AJ, Cunningham J, Priolo C, and Henske EP
- Subjects
- Cell Line, Homeostasis physiology, Humans, Intracellular Signaling Peptides and Proteins, Niemann-Pick C1 Protein, Carrier Proteins metabolism, Cholesterol metabolism, Lysosomes metabolism, Membrane Glycoproteins metabolism, Receptors, LDL metabolism, Tuberous Sclerosis metabolism
- Abstract
Tuberous sclerosis complex (TSC) is a multisystem disease associated with hyperactive mTORC1. The impact of TSC1/2 deficiency on lysosome-mediated processes is not fully understood. We report here that inhibition of lysosomal function using chloroquine (CQ) upregulates cholesterol homeostasis genes in TSC2-deficient cells. This TSC2-dependent transcriptional signature is associated with increased accumulation and intracellular levels of both total cholesterol and cholesterol esters. Unexpectedly, engaging this CQ-induced cholesterol uptake pathway together with inhibition of de novo cholesterol synthesis allows survival of TSC2-deficient, but not TSC2-expressing cells. The underlying mechanism of TSC2-deficient cell survival is dependent on exogenous cholesterol uptake via LDL-R, and endosomal trafficking mediated by Vps34. Simultaneous inhibition of lysosomal and endosomal trafficking inhibits uptake of esterified cholesterol and cell growth in TSC2-deficient, but not TSC2-expressing cells, highlighting the TSC-dependent lysosome-mediated regulation of cholesterol homeostasis and pointing toward the translational potential of these pathways for the therapy of TSC.
- Published
- 2017
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