The model of NOD2 vesicle-associated function. 1) Catalytically active V-ATPase consisting of transmembrane V0 and cytoplasmic V1 (big circle) sectors pumps (big dotted arrow) protons from the cytoplasm into the vesicle. Cytoplasmic NOD2 (grey figure) is in the self-inhibiting state; 2) NOD2 may substitute for the catalytic V1A subunit (stripped oval) in the V-ATPase complex, when pumping is stopped and the rest of V-ATPase complex remains assembled. 3) A normal membrane keeps sulfatide (black-head “lipid”) on the outer (opposite to the cytoplasm) leaflet. 4) When the membrane is damaged, it exposes sulfatide to the cytoplasm. 5) The sulfatide exposure to the cytoplasm is recognized by NOD2, which induces V-ATPase complex disassembly and opens the fusion-mediating V0 sector, making the vesicle fusion-competent.