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).
References:
The transmembrane (2 TMSs, N- and C-termini) Emp24 domain-containing protein 1, TMED1 of 227 aas.
Animals
TMED1 of Homo sapiens
Tmed10 of 209 aas and 2 TMSs, N- and C-terminal. Tmed10 deficiency results in impaired exocrine pancreatic differentiation in zebrafish larvae. The importance of appropriate beta-catenin signaling in exocrine pancreas development has been established (Tao et al. 2023).
Tmed10 of Danio rerio (alterntive names: Brachidanio rerio, Brachydanio rerio frankei, Cyprinus rerio. Danio frankei)
The transmembrane (2 TMSs, N- and C-termini) Emp24 domain-containing protein 2, TMED2 or RNP24 of 201 aas. A role for TMED2 in liver health has been suggested (Hou et al. 2017). The structure, topology, and dynamics of membrane-inserted polypeptides and lipids have been examined by solid-state NMR spectroscopy, specifically with respect to the transmembrane domains of the DQ Beta-1 subunit of the MHC II receptor and the COP I protein, p24 (Salnikov et al. 2019). The role of the p24/transmembrane emp24 domain (TMED) family of cargo receptors in development and disease has been reviewed (Aber et al. 2019). TMED2/emp24 is required in both the chorion and the allantois for placental labyrinth layer development involving membrane fusion (Hou and Jerome-Majewska 2018). Circular RNA circ_0008305 aggravates hepatocellular carcinoma growth through binding to miR-186 and inducing TMED2 (Zhang et al. 2022). TMED2 induces cisplatin resistance in breast cancer by targeting the KEAP1-Nrf2 pathway (Liang et al. 2023). TMED2 promotes glioma tumorigenesis by being involved in EGFR recycling transport (Sun et al. 2024).
Animals
TMED2 of Homo sapiens
The transmembrane (2 TMSs, N- and C-termini) Emp24 domain-containing protein 3, TMED3 of 217 aas. TMED3 plays a role in esophageal carcinomas (Kattner 2023). It has a potential role in vesicular protein trafficking, mainly in the early secretory pathway, and it contributes to the coupled localization of TMED2 and TMED10 in the cis-Golgi network (Emery et al. 2000). It may regulate the progression of breast cancer (Yang et al. 2023). TMED3 stabilizes SMAD2 by counteracting NEDD4-mediated ubiquitination to promote ovarian cancer (Chen et al. 2024).
Animals
TMED3 of Homo sapiens
Transmembrane emp24 domain-containing protein 10 precursor, Tmed10 or TMP21, of 219 aas and 2 TMSs, N- and C-terminal. It is involved in vesicular protein trafficking in the early secretory pathway, probably as a cargo receptor at the lumenal side for incorporation of secretory cargo molecules into transport vesicles (Luo et al. 2011). The TMP21 transmembrane domain promotes its association with the presenilin complex that results in decreased gamma-cleavage activity (Pardossi-Piquard et al. 2009). Thus, TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity (Chen et al. 2006). TMP21 modulates cell growth of papillary thyroid cancer cells by inducing autophagy through activation of the AMPK/mTOR pathway (Xu et al. 2015). TMED2 may regulate inflammation in lung adenocarcinoma (LUAD) through the TLR4/NF-kappaB signaling pathway and enhance the proliferation, development, and prognosis of LUAD by regulating inflammation (Feng et al. 2022). It is present in alterred amounts upon acute kidney damage following Covid-19 infection (Paranjpe et al. 2023). Transmembrane p24 trafficking protein 10 (TMED10) inhibits mitochondrial damage and protects neurons in ischemic stroke via the c-Jun N-terminal kinase (JNK) signaling pathway (Li et al. 2023). TMED10 mediates the trafficking of insulin-like growth factor 2 along the secretory pathway for myoblast differentiation (Li et al. 2023).
Tmed10 of Homo sapiens
Transmembrane emp24 domain-containing protein, eclair or Eca, of 216 aas and 2 TMSs, N- and C-terminal. Eca and Bai are essential, though not redundant, for dorsoventral patterning of the embryo. They are required during early embryogenesis for the activity of maternal Tkv receptor (TC# 8.B.23.1.27), while the zygotic Tkv is not affected (Bartoszewski et al. 2004). It may also be involved in Golgi organization (Kondylis et al. 2011). Ecla and Bai are involved in the early secretory pathway of Wingless/Wnt, but only Bai interacts with wingless (Wg) (Li et al. 2015).
EMP24 of Drosophila melanogaster (Fruit fly)
Transmembrane emp24 domain-containing protein Baiser or Bai, of 206 aas and 2 TMSs, N- and C-terminal. Eca (TC# 9.B.188.1.5) and Bai are essential, though not redundant, for dorsoventral patterning of the embryo (Bartoszewski et al. 2004). They are specifically required during early embryogenesis for the activity of the maternal Kkv receptor, while the zygotic Tkv is not affected. Ecla and Bai are involved in the early secretory pathway of Wingless/Wnt, but only Bai interacts with wingless (Wg) (Li et al. 2015).
Bai of Drosophila melanogaster
p24 protein (EMP24-1; GP25) of 210 aas and 2 TMSs, N- and C-terminal. It is a cargo receptor involved in ER to golgi vesticle transport (Carney and Bowen 2004). The p24/transmembrane emp24 domain (TMED) family of cargo receptors has been shown to be important in development and disease (Aber et al. 2019).
p24 of Drosophila melanogaster (Fruit fly)
Transmembrane emp24 domain-containing protein 7, TMED7, of 224 aas and 2 TMSs, N- and C-terminal. It plays a role in vesicular protein trafficking, mainly in
the early secretory pathway. It appears to function in the biosynthesis
of secreted cargo including processing and post-translational
modifications and thereby in embyogenesis (Nie et al. 2020).
TMED7 of Homo sapiens
Transmembrane emp24 domain-containing protein 9 of 235 aas and 2 TMSs, N- and C-terminal, TMED9. The secretory pathway is an intracellular highway for the vesicular transport of newly synthesized proteins that span the ER, Golgi, lysosome and cell surface membranes. A variety of cargo receptors, chaperones, and quality control proteins maintain the smooth flow of cargo along this route. Among these is vesicular transport protein TMED9, which belongs to the p24/transmembrane emp24 domain (TMED) family of proteins. It is expressed across vertebrate species (Roberts and Satpute-Krishnan 2022). The TMED family consists of structurally-related type I transmembrane proteins with a luminal N-terminal Golgi-dynamics domain, a luminal coiled-coil domain, a transmembrane domain and a short cytosolic C-terminal tail that binds COPI and COPII coat proteins. TMED9, like other members of the TMED family, was first identified as an abundant constituent of the COPI and COPII coated vesicles that mediate traffic between the ER and the Golgi. TMED9 is typically purified in hetero-oligomers together with TMED family members, suggesting that it may function as part of a complex. TMED family members play various roles in secretory pathway homeostasis including secreted protein processing, quality control and degradation of misfolded proteins, and post-Golgi trafficking. In particular, TMED9 has been implicated in autophagy, lysosomal sorting, viral replication and cancer (Roberts and Satpute-Krishnan 2022). TMED9, a member of the TMED/p24 family that transports, modifies, and packs proteins and lipids into vesicles for delivery to specific locations, is important in innate immune signaling via the ER-Golgi cargo pathway. TMED9 has been implicated in various cancer types, and is a prognostic biomarker for epithelial ovarian cancer (Han et al. 2022).
TMED9 of Homo sapiens