VAMP5 (vesicle-associated membrane protein 5) is a SNARE protein primarily functioning in exosome biogenesis and release through vesicular trafficking. As an R-SNARE localized to multivesicular bodies (MVBs), VAMP5 mediates MVB-plasma membrane fusion by interacting with Q-SNAREs including SNAP47, STX1, and STX4, enabling exosome secretion in both polarized and non-polarized cells 1. VAMP5 is post-translationally modified by S-palmitoylation, a reversible lipophilic modification regulating protein signaling 2. Beyond canonical exocytosis, VAMP5 functions as a cell-autonomous antiviral defense factor, localizing to double-membrane vesicles where it interacts with viral NSP8 to restrict coronavirus replication including SARS-CoV-2 and related pathogens 3. VAMP5 is highly expressed in embryonic stem cells and mesoderm, contributing to their inherent viral resistance 3. Clinical relevance includes associations with Hirschsprung disease susceptibility, particularly long-segment aganglionosis, through genetic polymorphisms (rs10206961, rs1254900) 4, and elevated expression as a diagnostic biomarker in tuberculosis (AUC 0.993) and nonalcoholic fatty liver disease-related hepatocellular carcinoma 56. VAMP5 is also released in extracellular vesicles by retinal Müller glia and responds to ischemic stress 7. VAMP5 shows no association with primary open-angle glaucoma in Dutch populations 8.