Regulation of intracellular membrane trafficking and cell dynamics by syntaxin-6

Abstract

Intracellular membrane trafficking along endocytic and secretory transport pathways plays a critical role in diverse cellular functions including both developmental and pathological processes. Briefly, proteins and lipids destined for transport to distinct locations are collectively assembled into vesicles and delivered to their target site by vesicular fusion. SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) proteins are required for these events, during which v-SNAREs (vesicle SNAREs) interact with t-SNAREs (target SNAREs) to allow transfer of cargo from donor vesicle to target membrane. Recently, the t-SNARE family member, syntaxin-6, has been shown to play an important role in the transport of proteins that are key to diverse cellular dynamic processes. In this paper, we briefly discuss the specific role of SNAREs in various mammalian cell types and comprehensively review the various roles of the Golgi- and endosome-localized t-SNARE, syntaxin-6, in membrane trafficking during physiological as well as pathological conditions.

The cross-talk of LDL-cholesterol with cell motility: Insights from the Niemann Pick Type C1 mutation and altered integrin trafficking

“…28,29 Further insight comes from Stx6, which participates in LE-cholesterol delivery to the ER, and regulates lipid and protein transport, including caveolin, required for caveolae endocytosis. 30 In HeLa and other cancer cell models, Stx6 depletion reduces caveolae numbers, impedes a3b1 and a5b1 integrin recycling and delivery of FAK to focal adhesions. 6,26,30 Stx6 predominantly interacts with VAMP4 in the TGN, but can shuttle to recycling endosomes and assemble with VAMP3.…”

“…30 In HeLa and other cancer cell models, Stx6 depletion reduces caveolae numbers, impedes a3b1 and a5b1 integrin recycling and delivery of FAK to focal adhesions. 6,26,30 Stx6 predominantly interacts with VAMP4 in the TGN, but can shuttle to recycling endosomes and assemble with VAMP3. 6,26,30 Most strikingly, cholesterol diminution in the Golgi of NPC1 mutant CHO cells triggered increased Stx6/VAMP3 assembly in recycling endosomes.…”

“…6,26,30 Stx6 predominantly interacts with VAMP4 in the TGN, but can shuttle to recycling endosomes and assemble with VAMP3. 6,26,30 Most strikingly, cholesterol diminution in the Golgi of NPC1 mutant CHO cells triggered increased Stx6/VAMP3 assembly in recycling endosomes. 6 Replenishment of Golgi cholesterol using LDL in NPC mutant cells induced Stx6 recruitment back to the TGN.…”

Role of cholesterol in SNARE-mediated trafficking on intracellular membranes

“…STX6 participates in various membrane fusion events with different SNARE complexes. Upon completion of membrane fusion, a tyrosine-based sorting motif (YGRL, position 140-143) located between the N-terminal domain and the SNARE motif is activated, which results in its re-sorting to the TGN (Jahn and Scheller, 2006;Jung et al, 2012). Importantly, STX6 binds to cholesterol (Hulce et al, 2013) and has been previously implicated in cholesterol transport; it contributes to the delivery of late-endosome-derived cholesterol to the ER via the TGN (Urano et al, 2008) and of lipids and proteins that are required for caveolae endocytosis to the plasma membrane (Choudhury et al, 2006).…”

Blood group antigen loci demonstrate multivariate genetic associations with circulating cellular adhesion protein levels in the Multi-Ethnic Study of Atherosclerosis

“…An intronic variant within uncharacterized protein gene KIAA1614 , rs7521237 has been previously reported to be a cis -eQTL of neighboring gene STX6 (syntaxin-6) in brain tissues(Zou et al 2012). Syntaxin-6 has been shown to play an important role in angiogenesis by regulating trafficking of VEGFR2 and α5β1 integrin within endothelial cells(Jung et al 2012), which in turn is regulated by cholesterol levels within the within the trans-Golgi network(Reverter et al 2014). Although rs17074898 was also evaluated in HIS, this SNP was not genome-wide significant (P = 0.05).…”