Lysosomal regulation of cholesterol homeostasis in tuberous sclerosis complex is mediated via NPC1 and LDL-R

Oncotarget
Harilaos FilippakisElizabeth P Henske

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.

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Citations

Jun 15, 2017·Oncotarget·Prashanth Gokare, Wafik S El-Deiry
Sep 21, 2018·Nature Reviews. Nephrology·Hilaire C LamElizabeth P Henske
Apr 10, 2020·JCI Insight·Alexander J ValvezanBrendan D Manning
Sep 23, 2018·Scientific Reports·Harilaos FilippakisElizabeth P Henske

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Methods Mentioned

BETA
PCR
transfection
xenograft

Software Mentioned

GraphPad Prism
1000
ImageJ

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