TMED10 is a transmembrane cargo receptor functioning as a critical mediator of protein trafficking between the endoplasmic reticulum (ER), ER-Golgi intermediate compartment (ERGIC), and Golgi apparatus 1. It operates through dual mechanisms: acting as a conventional cargo receptor for COPI and COPII-coated vesicles 1, and functioning as a protein channel facilitating translocation of leaderless cargo proteins lacking signal peptides into the ERGIC 2. TMED10 recognizes GPI-anchored proteins and directs their transport via SEC24C/D-dependent COPII vesicles, while also regulating retrograde transport and modulating ARF1-GTP hydrolysis on Golgi membranes 3. Beyond conventional secretion, TMED10 mediates unconventional secretion of functionally important leaderless proteins including IL-1 family members, galectins, and tau, with translocation dependent on protein unfolding and HSP90 chaperones 2. TMED10-mediated secretion has emerged as clinically significant: PTEN secretion via TMED10 drives antitumor immunity through macrophage activation 4, while TMED10 inhibition rescues trafficking defects in uromodulin-associated kidney disease 5. Additionally, coronavirus envelope proteins exploit TMED10 to enhance IL-1 secretion and inflammatory pathways 6. Genetic variants in TMED10 associate with hidradenitis suppurativa through disrupted keratinocyte signaling 7.