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9.B.420.  The Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) Family 

TREM2 forms a receptor signaling complex with TYROBP which mediates signaling and cell activation following ligand binding (Bouchon et al. 2000). It acts as a receptor for amyloid-beta protein 42, a cleavage product of the amyloid-beta precursor protein APP, and mediates its uptake and degradation by microglia (Yeh et al. 2016, Zhao et al. 2018). Binding to amyloid-beta 42 mediates microglial activation, proliferation, migration, apoptosis and expression of pro-inflammatory cytokines, such as IL6R and CCL3, and the anti-inflammatory cytokine ARG1. TREM2 acts as a receptor for lipoprotein particles such as LDL, VLDL, and HDL and for apolipoproteins such as APOA1, APOA2, APOB, APOE, APOE2, APOE3, APOE4, and CLU to enhance their uptake in microglia (Yeh et al. 2016). It also binds phospholipids (preferably anionic lipids) such as phosphatidylserine, phosphatidylglycerol and sphingomyelin (Sudom et al. 2018). It regulates microglial proliferation by acting as an upstream regulator of the Wnt/beta-catenin signaling cascade, and is required for microglial phagocytosis of apoptotic neurons (Kleinberger et al. 2014).

The polymeric immunoglobulin receptor, PIGR, of 764 aas and 2 TMSs, one N-terminal and one at residue 650, near the C-terminus, contains two repeats (residues 31 - 128 and 361 - 455). It mediates selective transcytosis of polymeric IgA and IgM across mucosal epithelial cells. It binds polymeric IgA and IgM at the basolateral surfaces of epithelial cells. The complex is then transported across the cell to be secreted at the apical surface. During this process, a cleavage occurs that separates the extracellular (known as the secretory component) from the transmembrane segment. Through its N-linked glycans, it ensures anchoring of secretory IgA (sIgA) molecules to mucus lining the epithelial surface to neutralize extracellular pathogens (Phalipon et al. 2002). On its own (free form) it may act as a non-specific microbial scavenger to prevent pathogen interactions with epithelial cells (Perrier et al. 2006). The regulatory functions of secretory immunoglobulins (i.e., sIgA) after transport across the membrane by pIgR in Bactrian camel (Camelus bactrianus) lungs (He et al. 2022).




This family belongs to the: Basigin-TREM2/PIGR Superfamily.

References associated with 9.B.420 family:

Bouchon, A., J. Dietrich, and M. Colonna. (2000). Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol 164: 4991-4995. 10799849
He, W.H., W.D. Zhang, C.C. Cheng, J. Lu, L. Liu, Z.H. Chen, and W.H. Wang. (2022). Expression characteristics of polymeric immunoglobulin receptor in Bactrian camel (Camelus bactrianus) lungs. PLoS One 17: e0264815. 35245335
Karsak, M., K. Glebov, M. Scheffold, T. Bajaj, A. Kawalia, I. Karaca, S. Rading, J. Kornhuber, O. Peters, M. Diez-Fairen, L. Frölich, M. Hüll, J. Wiltfang, M. Scherer, S. Riedel-Heller, A. Schneider, M.T. Heneka, K. Fliessbach, A. Sharaf, H. Thiele, M. Lennarz, F. Jessen, W. Maier, C. Kubisch, Z. Ignatova, P. Nürnberg, P. Pastor, J. Walter, and A. Ramirez. (2020). A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2. Hum Mutat 41: 169-181. 31464095
Kleinberger, G., Y. Yamanishi, M. Suárez-Calvet, E. Czirr, E. Lohmann, E. Cuyvers, H. Struyfs, N. Pettkus, A. Wenninger-Weinzierl, F. Mazaheri, S. Tahirovic, A. Lleó, D. Alcolea, J. Fortea, M. Willem, S. Lammich, J.L. Molinuevo, R. Sánchez-Valle, A. Antonell, A. Ramirez, M.T. Heneka, K. Sleegers, J. van der Zee, J.J. Martin, S. Engelborghs, A. Demirtas-Tatlidede, H. Zetterberg, C. Van Broeckhoven, H. Gurvit, T. Wyss-Coray, J. Hardy, M. Colonna, and C. Haass. (2014). TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 6: 243ra86. 24990881
Lok, H.C. and J.B. Kwok. (2021). The Role of White Matter Dysfunction and Leukoencephalopathy/Leukodystrophy Genes in the Aetiology of Frontotemporal Dementias: Implications for Novel Approaches to Therapeutics. Int J Mol Sci 22:. 33802612
Perrier, C., N. Sprenger, and B. Corthésy. (2006). Glycans on secretory component participate in innate protection against mucosal pathogens. J. Biol. Chem. 281: 14280-14287. 16543244
Phalipon, A., A. Cardona, J.P. Kraehenbuhl, L. Edelman, P.J. Sansonetti, and B. Corthésy. (2002). Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo. Immunity 17: 107-115. 12150896
Sudom, A., S. Talreja, J. Danao, E. Bragg, R. Kegel, X. Min, J. Richardson, Z. Zhang, N. Sharkov, E. Marcora, S. Thibault, J. Bradley, S. Wood, A.C. Lim, H. Chen, S. Wang, I.N. Foltz, S. Sambashivan, and Z. Wang. (2018). Molecular basis for the loss-of-function effects of the Alzheimer''s disease-associated R47H variant of the immune receptor TREM2. J. Biol. Chem. 293: 12634-12646. 29794134
Yeh, F.L., Y. Wang, I. Tom, L.C. Gonzalez, and M. Sheng. (2016). TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 91: 328-340. 27477018
Zhao, Y., X. Wu, X. Li, L.L. Jiang, X. Gui, Y. Liu, Y. Sun, B. Zhu, J.C. Piña-Crespo, M. Zhang, N. Zhang, X. Chen, G. Bu, Z. An, T.Y. Huang, and H. Xu. (2018). TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function. Neuron. 97: 1023-1031.e7. 29518356