Seminar: TMED-mediated unconventional secretion and its role in the regulation of meta-inflammation

Protein secretion is a fundamental cellular process that underpins intercellular communication. The classical secretory pathway relies on N-terminal signal peptides to direct proteins into the endoplasmic reticulum (ER) via the signal recognition particle (SRP) and SEC61 translocon, followed by trafficking through the ER-Golgi system. However, accumulating evidence has revealed a substantial number of secretory proteins that lack signal peptides—referred to as leaderless proteins—including members of the interleukin-1 family, galectins, and Tau. These proteins are exported via unconventional protein secretion (UcPS) pathways and are implicated in a wide range of pathophysiological processes, including inflammation, cancer, and neurodegeneration.Despite their biological significance, the mechanisms by which leaderless proteins are selectively recognized and translocated for secretion have remained largely elusive. Our previous work identified a novel translocation mechanism involving the transmembrane emp24 domain-containing (TMED) protein family, which mediates the entry of leaderless proteins into secretory vesicles. This TMED-dependent UcPS pathway has been implicated—by our group and others—in several disease contexts, including inflammatory bowel disease, coronavirus infection, cancer immunology, and neuronal homeostasis.In this presentation, I will highlight our recent advances in elucidating the molecular basis of TMED-mediated UcPS, discuss its regulatory mechanisms, and explore its functional role in the modulation of meta-inflammation.