8.A.218. 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). TREM2 exacerbates atherosclerosis development by promoting SMC- and macrophage-derived foam cell formation by regulating scavenger receptor CD36 expression and promoting cholesterol uptake (Guo et al. 2023).
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).
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TREM2 of 230 aas and 2 TMSs, N- and C-terminal. It plays a role in frontotemporal dementia (FTD) that is a common cause of presenile dementia and is characterized by behavioural and/or language changes leading to progressive cognitive deficits (Lok and Kwok 2021). A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2 (Karsak et al. 2020).
TREM of Homo sapiens
TREM-A1 of 221 aas and 2 TMSs, N- and C-terminal.
TREM-A2 of Gallus gallus (Chicken)
Fas apoptotic inhibitory molecule 3-like protein of 640 aas and 2 or 3 TMSs, with one or two TMSs at residues 160 - 200 and another at residues 570 - 590.
TREM-like protein of Bos taurus
Uncharacterized protein of 270 aas and 2 TMSs at residues 90 - 110 and 230 - 250.
UP of Ameiurus melas
Polymeric immunoglobulin receptor of 909 aas and 2 TMSs, one N-terminal and one near the C-terminus at residues 780 - 805. The central part (residues 150 - 330) of this protein may be distantly related to fibroblast growth factor receptor-like protein, FGFRL1 (TC# 8.A.23.1.6).
IgG receptor of Myotis brandtii
Natural cytotoxicity triggering receptor 2 of 300 aas with two TMSs, one N-terminal and one near the C-terminus at residues 200 - 220.
Receptor of Camelus bactrianus
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).
PIGR of Homo sapiens
Polymeric immunoglobulin receptor (pIgR) of 336 aas and two TMSs, one at the N-terminus of the protein and one at about residues 270 - 290, near the C-terminus. pIgR can bind and transport immunoglobulins (Igs), thus playing a role in mucosal immunity (Ji et al. 2023). The pIgR protein consists of a signal peptide, an extracellular domain, a transmembrane domain and an intracellular region, with the presence of two Ig-like domains (ILDs) in the extracellular domain.
pIgR of Siniperca chuatsi, the mandarin fish