Cholesterol regulates Syntaxin 6 trafficking at trans-Golgi network endosomal boundaries

Cell Rep. 2014 May 8;7(3):883-97. doi: 10.1016/j.celrep.2014.03.043. Epub 2014 Apr 17.

Abstract

Inhibition of cholesterol export from late endosomes causes cellular cholesterol imbalance, including cholesterol depletion in the trans-Golgi network (TGN). Here, using Chinese hamster ovary (CHO) Niemann-Pick type C1 (NPC1) mutant cell lines and human NPC1 mutant fibroblasts, we show that altered cholesterol levels at the TGN/endosome boundaries trigger Syntaxin 6 (Stx6) accumulation into VAMP3, transferrin, and Rab11-positive recycling endosomes (REs). This increases Stx6/VAMP3 interaction and interferes with the recycling of αVβ3 and α5β1 integrins and cell migration, possibly in a Stx6-dependent manner. In NPC1 mutant cells, restoration of cholesterol levels in the TGN, but not inhibition of VAMP3, restores the steady-state localization of Stx6 in the TGN. Furthermore, elevation of RE cholesterol is associated with increased amounts of Stx6 in RE. Hence, the fine-tuning of cholesterol levels at the TGN-RE boundaries together with a subset of cholesterol-sensitive SNARE proteins may play a regulatory role in cell migration and invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Movement
  • Cholesterol / metabolism*
  • Cricetinae
  • Cricetulus
  • Endosomes / metabolism*
  • Humans
  • Integrin alpha5beta1 / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Protein Binding
  • Protein Transport
  • Qa-SNARE Proteins / chemistry
  • Qa-SNARE Proteins / metabolism*
  • Receptors, Vitronectin / metabolism
  • SNARE Proteins / metabolism
  • Vesicle-Associated Membrane Protein 3 / chemistry
  • Vesicle-Associated Membrane Protein 3 / metabolism
  • rab GTP-Binding Proteins / metabolism
  • trans-Golgi Network / metabolism*

Substances

  • Carrier Proteins
  • Integrin alpha5beta1
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • Qa-SNARE Proteins
  • Receptors, Vitronectin
  • SNARE Proteins
  • Vesicle-Associated Membrane Protein 3
  • integrin alphavbeta1
  • Cholesterol
  • rab11 protein
  • rab GTP-Binding Proteins