The trans‐SNARE complex VAMP4/Stx6/Stx7/Vti1b is a key regulator of Golgi to late endosome MT1‐MMP transport in macrophages

Abstract

The activity of the matrix metalloproteinase (MMP) MT1‐MMP is strictly regulated by expression and cellular location. In macrophages LPS activation leads to the up‐regulation of MT1‐MMP and this need to be at the cell surface for them to degrade the dense extracellular matrix (ECM) components to create a path to migrate into injured and infected tissues. Fixed and live imaging shows newly made MT1‐MMP is packaged into vesicles that traffic to and fuse with LBPA+LAMP1+ late endosomes en route to the surface. The R‐SNARE VAMP4, found on Golgi‐derived vesicles that traffic to late endosomes, forms a trans‐SNARE complex with the Q‐SNARE complex Stx6/Stx7/Vti1b. The Stx6/Stx7/Vti1b complex has been shown to be up‐regulated in lipopolysaccharide (LPS)‐activated cells to increase trafficking of key cytokines through the classical pathway and now we show here it is up‐regulation also plays a role in the late endosomal pathway of MT1‐MMP trafficking. Depletion of any of the SNAREs in this complex reduces surface MT1‐MMP and gelatin degradation. Conversely, overexpression of the Stx6/Stx7/Vti1b components increases surface MT1‐MMP levels. This suggests that Stx6/Stx7/Vti1b is a key Q‐SNARE complex in macrophages during an immune response and in partnership with VAMP4 it regulates transport of newly made MT1‐MMP.