Role of cholesterol in SNARE-mediated trafficking on intracellular membranes

Abstract

The cell surface delivery of extracellular matrix (ECM) and integrins is fundamental for cell migration in wound healing and during cancer cell metastasis. This process is not only driven by several soluble NSF attachment protein (SNAP) receptor (SNARE) proteins, which are key players in vesicle transport at the cell surface and intracellular compartments, but is also tightly modulated by cholesterol. Cholesterol-sensitive SNAREs at the cell surface are relatively well characterized, but it is less well understood how altered cholesterol levels in intracellular compartments impact on SNARE localization and function. Recent insights from structural biology, protein chemistry and cell microscopy have suggested that a subset of the SNAREs engaged in exocytic and retrograde pathways dynamically 'sense' cholesterol levels in the Golgi and endosomal membranes. Hence, the transport routes that modulate cellular cholesterol distribution appear to trigger not only a change in the location and functioning of SNAREs at the cell surface but also in endomembranes. In this Commentary, we will discuss how disrupted cholesterol transport through the Golgi and endosomal compartments ultimately controls SNARE-mediated delivery of ECM and integrins to the cell surface and, consequently, cell migration.

The Role of Cholesterol in Cancer

“…Melanoma cells were more sensitive to inhibition of intracellular cholesterol transport than normal skin cells suggesting this agent could be a useful therapeutic agent (61). Intracellular cholesterol transport inhibitors could also inhibit tumor cell metastasis by interfering with cholesterol levels in the trans-golgi network and reducing cell surface expression of integrins that are fundamental for cancer cell migration during metastasis (62,66,67). However, the potential of agents like leelamine to inhibit metastasis of melanoma cells remains to be demonstrated.…”

The role of cholesterol in membrane fusion

“…CARC and CRAC motifs have been identified in several, but by no means all (actually in 11 of 38 human) SNARE proteins (Enrich et al, 2015). Their presence or absence does not seem to correlate with the cholesterol content of the membrane in which these SNAREs reside, raising questions on their functional relevance.…”

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

“…34,35 Besides Stx4/ SNAP23, Stx6 and VAMP3 (see above), VAMP2 also participates in transport and recycling of a5, a3, b1 integrin and FAK, 26 while Stx12 together with SNAP23 is required for Src and b1 integrin transport to cholesterol-rich invadopodia for cell invasion. 29 These regulatory circuits seem to exist in various cancer cell lines, and it is tempting to speculate that all these SNAREs in a large number of cells may respond to temporal and local changes in LDL-or HDL-cholesterol delivery.…”