9.B.188 The Transmembrane Emp24 Domain-containing Protein (TMED) Family 

Members of this family are involved in vesicular protein trafficking and mainly function in the early secretory pathway, but also in post-Golgi membranes. They are thought to act as cargo receptors at the lumenal side for incorporation of secretory cargo molecules into transport vesicles and to be involved in vesicle coat formation at the cytoplasmic side. In COPII vesicle-mediated anterograde transport, they are involved in the transport of GPI-anchored proteins and are proposed to act together with TMED10 as cargo receptors; the function specifically implies SEC24C and SEC24D of the COPII vesicle coat and lipid raft-like microdomains of the ER. They recognize GPI anchors, structurally remodeled in the ER by PGAP1 and MPPE1. COPI vesicle-mediated retrograde transport inhibits the GTPase-activating activity of ARFGAP1 towards ARF1, thus preventing immature uncoating and allowing cargo selection to take place. They are involved in trafficking of G protein-coupled receptors (GPCRs) and regulating F2RL1, OPRM1 and P2RY4 exocytic trafficking from the Golgi to the plasma membrane, thus contributing to receptor resensitization. They facilitate CASR maturation and stabilization in the early secretory pathway while increasing CASR plasma membrane targeting. They may be involved in the organization of intracellular membranes such as the maintenance of the Golgi apparatus and may play a role in the biosynthesis of secreted cargo, i.e., eventual processing (Beck et al. 2009). The p24/transmembrane emp24 domain (TMED) family of cargo receptors has been shown to be important in development and disease and has been reviewed (Aber et al. 2019). The members of the transmembrane emp24 domain-containing protein (TMED) family are found in four subfamilies, alpha (TMED 4, 9), beta (TMED 2), gamma (TMED1, 3, 5, 6, 7) and delta (TMED 10), with a total of nine members, which are important regulators of intracellular protein transport and are involved in normal embryonic development, as well as in the pathogenic processes of many human diseases including many forms of cancer (Zhou et al. 2023).

TMED proteins, also called p24 proteins, are members of a family of sorting receptors present in all representatives of the Eukarya and are abundantly present in all subcompartments of the early secretory pathway, namely the endoplasmic reticulum (ER), the Golgi, and the intermediate compartment. They are essential during the bidirectional transport between the ER and the Golgi. Mota et al. 2021 described the high-resolution structure of a TMED1 Golgi Dynamics (GOLD) representative and its biophysical characterization in solution. The crystal structure showed  dimer formation that is present in solution in a salt-dependent manner, suggesting that the GOLD domain can form homodimers in solution, even in the absence of the TMED1 coiled-coil region. There are 8 TMED homologues in C. elegans.  A functional protein from each subfamily is important for a shared set of developmental processes. A specific function for TMED genes is to facilitate breakdown of the basement membrane between the somatic gonad and vulval epithelial cells, suggesting a role for TMED proteins in tissue reorganization during animal development (Navarro and Chamberlin 2023). Association of TMED2 and TMED7 with TLRs facilitates anterograde transport from the ER to the Golgi (Holm et al. 2023). 

TMED proteins play a critical role in the ER stress-associated unconvential protein secretion (UPS) of transmembrane proteins (Park et al. 2022). The gene silencing results reveal that TMED2, TMED3, TMED9 and TMED10 are involved in the UPS of transmembrane proteins, such as CFTR, pendrin and SARS-CoV-2 Spike. Subsequent mechanistic analyses indicated that TMED3 recognizes the ER core-glycosylated protein cargos and that the heteromeric TMED2/3/9/10 complex mediates their UPS. Co-expression of all four TMEDs improves, while each single expression reduces, the UPS and ion transport function of trafficking-deficient ΔF508-CFTR and p.H723R-pendrin, which cause cystic fibrosis and Pendred syndrome, respectively. In contrast, TMED2/3/9/10 silencing reduces SARS-CoV-2 viral release. These results provide evidence for a common role of TMED3 and related TMEDs in the ER stress-associated, Golgi-independent secretion of transmembrane proteins (Park et al. 2022).