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

Oncotarget. 2017 Jun 13;8(24):38099-38112. doi: 10.18632/oncotarget.17485.

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.

Keywords: TSC; chloroquine; cholesterol; lysosome; mTORC1.

MeSH terms

  • Carrier Proteins / metabolism*
  • Cell Line
  • Cholesterol / metabolism*
  • Homeostasis / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lysosomes / metabolism*
  • Membrane Glycoproteins / metabolism*
  • Niemann-Pick C1 Protein
  • Receptors, LDL / metabolism*
  • Tuberous Sclerosis / metabolism*

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • Niemann-Pick C1 Protein
  • Receptors, LDL
  • Cholesterol