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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).


References associated with 9.B.188 family:

Aber, R., W. Chan, S. Mugisha, and L.A. Jerome-Majewska. (2019). Transmembrane emp24 domain proteins in development and disease. Genet Res (Camb) 101: e14. 31878985
Bartoszewski, S., S. Luschnig, I. Desjeux, J. Grosshans, and C. Nüsslein-Volhard. (2004). Drosophila p24 homologues eclair and baiser are necessary for the activity of the maternally expressed Tkv receptor during early embryogenesis. Mech Dev 121: 1259-1273. 15327786
Carney, G.E. and N.J. Bowen. (2004). p24 proteins, intracellular trafficking, and behavior: Drosophila melanogaster provides insights and opportunities. Biol Cell 96: 271-278. 15145531
Chen, F., H. Hasegawa, G. Schmitt-Ulms, T. Kawarai, C. Bohm, T. Katayama, Y. Gu, N. Sanjo, M. Glista, E. Rogaeva, Y. Wakutani, R. Pardossi-Piquard, X. Ruan, A. Tandon, F. Checler, P. Marambaud, K. Hansen, D. Westaway, P. St George-Hyslop, and P. Fraser. (2006). TMP21 is a presenilin complex component that modulates γ-secretase but not ε-secretase activity. Nature 440: 1208-1212. 16641999
Emery, G., M. Rojo, and J. Gruenberg. (2000). Coupled transport of p24 family members. J Cell Sci 113(Pt13): 2507-2516. 10852829
Feng, L., P. Cheng, Z. Feng, and X. Zhang. (2022). Transmembrane p24 trafficking protein 2 regulates inflammation through the TLR4/NF-κB signaling pathway in lung adenocarcinoma. World J Surg Oncol 20: 32. 35135563
Han, G.H., H. Yun, J.Y. Chung, J.H. Kim, and H. Cho. (2022). Expression Level as a Biomarker of Epithelial Ovarian Cancer Progression and Prognosis. Cancer Genomics Proteomics 19: 692-702. 36316042
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Hou, W. and L.A. Jerome-Majewska. (2018). TMED2/emp24 is required in both the chorion and the allantois for placental labyrinth layer development. Dev Biol 444: 20-32. 30236446
Hou, W., S. Gupta, M.C. Beauchamp, L. Yuan, and L.A. Jerome-Majewska. (2017). Non-alcoholic fatty liver disease in mice with heterozygous mutation in TMED2. PLoS One 12: e0182995. 28797121
Kattner, A.A. (2023). When it doesn''t run in the blood(vessels) - events involved in vascular disorders. Biomed J 46: 100591. 37059363
Kondylis, V., Y. Tang, F. Fuchs, M. Boutros, and C. Rabouille. (2011). Identification of ER proteins involved in the functional organisation of the early secretory pathway in Drosophila cells by a targeted RNAi screen. PLoS One 6: e17173. 21383842
Li, Q., X. Liu, R. Xing, and R. Sui. (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. Exp Anim 72: 151-163. 36244749
Li, T., F. Yang, Y. Heng, S. Zhou, G. Wang, J. Wang, J. Wang, X. Chen, Z.P. Yao, Z. Wu, and Y. Guo. (2023). TMED10 mediates the trafficking of insulin-like growth factor 2 along the secretory pathway for myoblast differentiation. Proc. Natl. Acad. Sci. USA 120: e2215285120. 37931110
Li, X., Y. Wu, C. Shen, T.Y. Belenkaya, L. Ray, and X. Lin. (2015). Drosophila p24 and Sec22 regulate Wingless trafficking in the early secretory pathway. Biochem. Biophys. Res. Commun. 463: 483-489. 26002470
Liang, C., H.Y. Zhang, Y.Q. Wang, L.A. Yang, Y.S. Du, Y. Luo, T.C. Zhang, and Y. Xu. (2023). TMED2 Induces Cisplatin Resistance in Breast Cancer via Targeting the KEAP1-Nrf2 Pathway. Curr Med Sci. [Epub: Ahead of Print] 37615927
Luo, W., Y. Wang, and G. Reiser. (2011). Proteinase-activated receptors, nucleotide P2Y receptors, and μ-opioid receptor-1B are under the control of the type I transmembrane proteins p23 and p24A in post-Golgi trafficking. J Neurochem 117: 71-81. 21219331
Mota, D.C.A.M., I.A. Cardoso, R.M. Mori, M.R.B. Batista, L.G.M. Basso, M.C. Nonato, A.J. Costa-Filho, and L.F.S. Mendes. (2021). Structural and thermodynamic analyses of human TMED1 (p24γ1) Golgi dynamics. Biochimie. [Epub: Ahead of Print] 34634369
Navarro, K.G. and H.M. Chamberlin. (2023). Genetic characterization of C. elegans TMED genes. Dev Dyn. [Epub: Ahead of Print] 37204056
Nie, Z.W., Y.J. Niu, W. Zhou, D.J. Zhou, J.Y. Kim, and X.S. Cui. (2020). AGS3-dependent TGN-membrane trafficking is essential for compaction in mouse embryos. J Cell Sci. [Epub: Ahead of Print] 33148610
Paranjpe, I., P. Jayaraman, C.Y. Su, S. Zhou, S. Chen, R. Thompson, D.M. Del Valle, E. Kenigsberg, S. Zhao, S. Jaladanki, K. Chaudhary, S. Ascolillo, A. Vaid, E. Gonzalez-Kozlova, J. Kauffman, A. Kumar, M. Paranjpe, R.O. Hagan, S. Kamat, F.F. Gulamali, H. Xie, J. Harris, M. Patel, K. Argueta, C. Batchelor, K. Nie, S. Dellepiane, L. Scott, M.A. Levin, J.C. He, M. Suarez-Farinas, S.G. Coca, L. Chan, E.U. Azeloglu, E. Schadt, N. Beckmann, S. Gnjatic, M. Merad, S. Kim-Schulze, B. Richards, B.S. Glicksberg, A.W. Charney, and G.N. Nadkarni. (2023). Proteomic characterization of acute kidney injury in patients hospitalized with SARS-CoV2 infection. Commun Med (Lond) 3: 81. 37308534
Pardossi-Piquard, R., C. Böhm, F. Chen, S. Kanemoto, F. Checler, G. Schmitt-Ulms, P. St George-Hyslop, and P.E. Fraser. (2009). TMP21 transmembrane domain regulates γ-secretase cleavage. J. Biol. Chem. 284: 28634-28641. 19710022
Roberts, B.S. and P. Satpute-Krishnan. (2022). The many hats of transmembrane emp24 domain protein TMED9 in secretory pathway homeostasis. Front Cell Dev Biol 10: 1096899. 36733337
Salnikov, E.S., C. Aisenbrey, B. Pokrandt, B. Brügger, and B. Bechinger. (2019). Structure, Topology, and Dynamics of Membrane-Inserted Polypeptides and Lipids by Solid-State NMR Spectroscopy: Investigations of the Transmembrane Domains of the DQ Beta-1 Subunit of the MHC II Receptor and of the COP I Protein p24. Front Mol Biosci 6: 83. 31608287
Sun, C., Y. Zhang, Z. Wang, J. Chen, J. Zhang, and Y. Gu. (2024). TMED2 promotes glioma tumorigenesis by being involved in EGFR recycling transport. Int J Biol Macromol 262: 130055. [Epub: Ahead of Print] 38354922
Tao, Z., D. Yang, and R. Ni. (2023). Tmed10 deficiency results in impaired exocrine pancreatic differentiation in zebrafish larvae. Dev Biol 503: 43-52. 37597605
Xu, X., H. Gao, J. Qin, L. He, and W. Liu. (2015). TMP21 modulates cell growth in papillary thyroid cancer cells by inducing autophagy through activation of the AMPK/mTOR pathway. Int J Clin Exp Pathol 8: 10824-10831. 26617795
Yang, C., M. Wang, R. Huang, L. Ou, M. Li, W. Wu, and R. Lei. (2023). Circ_0108942 Regulates the Progression of Breast Cancer by Regulating the MiR-1178-3p/TMED3 Axis. Clin Breast Cancer 23: 291-301. 36764873
Zhang, X., H.H. Hao, H.W. Zhuang, J. Wang, Y. Sheng, F. Xu, J. Dou, C. Chen, and Y. Shen. (2022). Circular RNA circ_0008305 aggravates hepatocellular carcinoma growth through binding to miR-186 and inducing TMED2. J Cell Mol Med 26: 1742-1753. 33210454
Zhou, L., H. Li, H. Yao, X. Dai, P. Gao, and H. Cheng. (2023). TMED family genes and their roles in human diseases. Int J Med Sci 20: 1732-1743. 37928880