TSPAN5 is a tetraspanin family member of the TspanC8 subgroup that functions as a critical regulator of ADAM10 metalloprotease trafficking and substrate specificity 1. TSPAN5 directly interacts with ADAM10 in the endoplasmic reticulum, promoting its exit and subsequent trafficking to the cell surface while determining which substrates ADAM10 cleaves 2. TSPAN5 associates with MHC class I molecules from the endoplasmic reticulum to the plasma membrane, facilitating their clustering into nanoclusters required for optimal CD8 T cell activation 3. Clinically, TSPAN5 has multiple disease relevances. In vascular biology, TSPAN5-ADAM10 complexes regulate VE-cadherin expression in endothelial cells, promoting T lymphocyte transmigration across the endothelium 1. In psychiatry, TSPAN5 genetic variants associate with plasma serotonin concentrations and selective serotonin reuptake inhibitor (SSRI) treatment outcomes in major depressive disorder 4. TSPAN5 also modulates serotonin and kynurenine levels in alcohol use disorder, with variants associated with acamprosate treatment response 5. Additionally, TSPAN5 variants influence Kawasaki disease susceptibility and intravenous immunoglobulin resistance 6. In oncology, elevated TSPAN5 expression correlates with poor colorectal cancer prognosis and promotes cancer cell proliferation, migration, and invasion 7.