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

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 year

  2014

• Venue

  Cell Reports

• Publication date

  2014-05-08

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.celrep.2014.03.043PMID 24746815
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Regulation of integrin endocytic recycling and chemotactic cell migration by syntaxin 6 and VAMP3 interaction

  2012influential reference
• Vesicular traffic in cell navigation

  2011cited by this paper
• Syntaxins 3 and 4 mediate vesicular trafficking of α5β1 and α3β1 integrins and cancer cell migration.

  2011cited by this paper
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  2011influential reference
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  2011influential reference
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  2011influential reference
• Requirement of Npc1 and availability of cholesterol for early embryonic cell movements in zebrafish[S]

  2011cited by this paper
• Spatial regulation of RhoA activity during pancreatic cancer cell invasion driven by mutant p53.

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  2010influential reference
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  2010cited by this paper
• Recycling Endosome Membrane Incorporation into the Leading Edge Regulates Lamellipodia Formation and Macrophage Migration

  2010cited by this paper
• Silencing of VAMP3 inhibits cell migration and integrin-mediated adhesion.

  2009cited by this paper
• Mutant p53 drives invasion by promoting integrin recycling.

  2009cited by this paper
• Intracellular sterol dynamics.

  2009cited by this paper
• Integrins: masters and slaves of endocytic transport

  2009cited by this paper
• Cellular cholesterol trafficking and compartmentalization

  2008cited by this paper
• Annexin A6-induced Inhibition of Cytoplasmic Phospholipase A2 Is Linked to Caveolin-1 Export from the Golgi*

  2008cited by this paper
• Endocytic transport of integrins during cell migration and invasion.

  2008cited by this paper
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  2008cited by this paper
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  2008cited by this paper
• VAMP4 cycles from the cell surface to the trans-Golgi network via sorting and recycling endosomes

  2007influential reference
• Annexin A6-Induced Alterations in Cholesterol Transport and Caveolin Export from the Golgi Complex

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• SNARE proteins and ‘membrane rafts’

  2007cited by this paper
• Changes in cholesterol levels in the plasma membrane modulate cell signaling and regulate cell adhesion and migration on fibronectin.

  2007influential reference
• Regulation of caveolar endocytosis by syntaxin 6-dependent delivery of membrane components to the cell surface

  2006cited by this paper
• Mechanisms for cellular cholesterol transport: defects and human disease.

  2006cited by this paper
• Faculty Opinions recommendation of Small GTPase Rab21 regulates cell adhesion and controls endosomal traffic of beta1-integrins.

  2006cited by this paper
• Integrin Trafficking and the Control of Cell Migration

  2006cited by this paper
• Small GTPase Rab21 regulates cell adhesion and controls endosomal traffic of β1-integrins

  2006cited by this paper
• Endocytic recycling pathways: emerging regulators of cell migration.

  2006cited by this paper
• Integrin traffic

  2006cited by this paper
• [Tetanus neurotoxin-mediated cleavage of cellubrevin impairs epithelial cell migration and integrin-dependent cell adhesion].

  2005influential reference
• Tetanus neurotoxin-mediated cleavage of cellubrevin impairs epithelial cell migration and integrin-dependent cell adhesion.

  2005cited by this paper
• Inhibition of SNARE-mediated membrane traffic impairs cell migration.

  2005cited by this paper
• Cholesterol and fatty acids regulate dynamic caveolin trafficking through the Golgi complex and between the cell surface and lipid bodies.

  2005cited by this paper
• SNARE-mediated trafficking of alpha5beta1 integrin is required for spreading in CHO cells.

  2005influential reference
• A Role for the Phagosome in Cytokine Secretion

  2005cited by this paper
• The Sterol-sensing Domain of the Niemann-Pick C1 (NPC1) Protein Regulates Trafficking of Low Density Lipoprotein Cholesterol*

  2005influential reference
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  2005cited by this paper
• Impaired Recycling of Apolipoprotein E4 Is Associated with Intracellular Cholesterol Accumulation*

  2004cited by this paper
• Binding between the Niemann-Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain.

  2004influential reference
• Elevated endosomal cholesterol levels in Niemann-Pick cells inhibit rab4 and perturb membrane recycling.

  2004influential reference
• Stimulation‐Dependent Recycling of Integrin β1 Regulated by ARF6 and Rab11

  2004influential reference
• Endocytic recycling

  2004cited by this paper
• Recycling Compartments and the Internal Vesicles of Multivesicular Bodies Harbor Most of the Cholesterol Found in the Endocytic Pathway

  2003cited by this paper
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  2003cited by this paper
• Early/recycling endosomes-to-TGN transport involves two SNARE complexes and a Rab6 isoform

  2002cited by this paper
• Modulation of cellular cholesterol transport and homeostasis by Rab11.

  2002cited by this paper
• Niemann-Pick C1 protein regulates cholesterol transport to the trans-Golgi network and plasma membrane caveolae.

  2002cited by this paper
• Vesicular and Non-vesicular Sterol Transport in Living Cells

  2002cited by this paper
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  2001cited by this paper
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  2001cited by this paper
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  2001cited by this paper
• PDGF-regulated rab4-dependent recycling of alphavbeta3 integrin from early endosomes is necessary for cell adhesion and spreading.

  2001influential reference
• PDGF-regulated rab4-dependent recycling of αvβ3 integrin from early endosomes is necessary for cell adhesion and spreading

  2001influential reference
• Niemann-Pick Type C1 (NPC1) Overexpression Alters Cellular Cholesterol Homeostasis*

  2000cited by this paper
• Cholesterol is Required for the Formation of Regulated and Constitutive Secretory Vesicles from the trans‐Golgi Network

  2000cited by this paper
• How cells handle cholesterol.

  2000cited by this paper
• Role of Cholesterol in Formation and Function of a Signaling Complex Involving αvβ3, Integrin-Associated Protein (Cd47), and Heterotrimeric G Proteins

  1999cited by this paper
• The Rab5 Effector EEA1 Interacts Directly with Syntaxin-6*

  1999cited by this paper
• Syntaxin 6 functions in trans-Golgi network vesicle trafficking.

  1997cited by this paper
• Differential accumulation of cholesterol in Golgi compartments of normal and Niemann-Pick type C fibroblasts incubated with LDL: a cytochemical freeze-fracture study.

  1993influential reference
• Cellubrevin is a ubiquitous tetanus-toxin substrate homologous to a putative synaptic vesicle fusion protein

  1993cited by this paper
• Isolation and characterization of Chinese hamster ovary cells defective in the intracellular metabolism of low density lipoprotein-derived cholesterol.

  1992cited by this paper
• The intracellular transport of low density lipoprotein-derived cholesterol is inhibited in Chinese hamster ovary cells cultured with 3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one.

  1989cited by this paper
• Type-C Niemann-Pick disease: low density lipoprotein uptake is associated with premature cholesterol accumulation in the Golgi complex and excessive cholesterol storage in lysosomes.

  1988cited by this paper

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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2017cites this paper
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  2017cites this paper
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  2017cites this paper
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  2017cites this paper
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  2017cites this paper
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  2016cites this paper
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  2016cites this paper
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  2016cites this paper
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  2016cites this paper
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  2016cites this paper
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  2016cites this paper
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  2016cites this paper
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  2015cites this paper
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