ID TREM2_HUMAN Reviewed; 230 AA. AC Q9NZC2; Q8N5H8; Q8WYN6; DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 28-JAN-2026, entry version 185. DE RecName: Full=Triggering receptor expressed on myeloid cells 2; DE Short=TREM-2; DE AltName: Full=Triggering receptor expressed on monocytes 2; DE Flags: Precursor; GN Name=TREM2 {ECO:0000312|HGNC:HGNC:17761}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=10799849; DOI=10.4049/jimmunol.164.10.4991; RA Bouchon A., Dietrich J., Colonna M.; RT "Inflammatory responses can be triggered by TREM-1, a novel receptor RT expressed on neutrophils and monocytes."; RL J. Immunol. 164:4991-4995(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RA Begum N.A., Tsukasa S.; RT "Identification of a novel variant of triggering receptor, TREM-2V, by mRNA RT differential display."; RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP FUNCTION, AND INTERACTION WITH TYROBP. RX PubMed=11602640; DOI=10.1084/jem.194.8.1111; RA Bouchon A., Hernandez-Munain C., Cella M., Colonna M.; RT "A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 RT and maturation of human dendritic cells."; RL J. Exp. Med. 194:1111-1122(2001). RN [5] RP TISSUE SPECIFICITY, INVOLVEMENT IN PLOSL2, AND VARIANTS PLOSL2 RP 44-TRP--THR-230 DEL; 78-TRP--THR-230 DEL; GLY-134 AND ASN-186. RX PubMed=12080485; DOI=10.1086/342259; RA Paloneva J., Manninen T., Christman G., Hovanes K., Mandelin J., RA Adolfsson R., Bianchin M., Bird T., Miranda R., Salmaggi A., RA Tranebjaerg L., Konttinen Y., Peltonen L.; RT "Mutations in two genes encoding different subunits of a receptor signaling RT complex result in an identical disease phenotype."; RL Am. J. Hum. Genet. 71:656-662(2002). RN [6] RP ERRATUM OF PUBMED:12080485. RA Paloneva J., Manninen T., Christman G., Hovanes K., Mandelin J., RA Adolfsson R., Bianchin M., Bird T., Miranda R., Salmaggi A., RA Tranebjaerg L., Konttinen Y., Peltonen L.; RL Am. J. Hum. Genet. 72:225-225(2003). RN [7] RP FUNCTION, INVOLVEMENT IN PLOSL2, VARIANT PLOSL2 14-GLU--THR-230 DEL, AND RP CHARACTERIZATION OF VARIANT PLOSL2 14-GLU--THR-230 DEL. RX PubMed=12925681; DOI=10.1084/jem.20030027; RA Paloneva J., Mandelin J., Kiialainen A., Bohling T., Prudlo J., Hakola P., RA Haltia M., Konttinen Y.T., Peltonen L.; RT "DAP12/TREM2 deficiency results in impaired osteoclast differentiation and RT osteoporotic features."; RL J. Exp. Med. 198:669-675(2003). RN [8] RP INVOLVEMENT IN PLOSL2, AND VARIANTS PLOSL2 33-GLN--THR-230 DEL AND GLY-126. RX PubMed=15883308; DOI=10.1212/01.wnl.0000160304.00003.ca; RA Kluenemann H.H., Ridha B.H., Magy L., Wherrett J.R., Hemelsoet D.M., RA Keen R.W., De Bleecker J.L., Rossor M.N., Marienhagen J., Klein H.E., RA Peltonen L., Paloneva J.; RT "The genetic causes of basal ganglia calcification, dementia, and bone RT cysts: DAP12 and TREM2."; RL Neurology 64:1502-1507(2005). RN [9] RP FUNCTION. RX PubMed=18957693; DOI=10.1126/scisignal.1159665; RA Helming L., Tomasello E., Kyriakides T.R., Martinez F.O., Takai T., RA Gordon S., Vivier E.; RT "Essential role of DAP12 signaling in macrophage programming into a fusion- RT competent state."; RL Sci. Signal. 1:RA11-RA11(2008). RN [10] RP INTERACTION WITH TYROBP. RX PubMed=25957402; DOI=10.1074/jbc.m115.645986; RA Zhong L., Chen X.F., Zhang Z.L., Wang Z., Shi X.Z., Xu K., Zhang Y.W., RA Xu H., Bu G.; RT "DAP12 stabilizes the C-terminal fragment of the triggering receptor RT expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro- RT inflammatory response."; RL J. Biol. Chem. 290:15866-15877(2015). RN [11] RP SUBCELLULAR LOCATION, AND PROTEOLYTIC PROCESSING. RX PubMed=24078628; DOI=10.1074/jbc.m113.517540; RA Wunderlich P., Glebov K., Kemmerling N., Tien N.T., Neumann H., Walter J.; RT "Sequential proteolytic processing of the triggering receptor expressed on RT myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase- RT dependent intramembranous cleavage."; RL J. Biol. Chem. 288:33027-33036(2013). RN [12] RP FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, CHARACTERIZATION OF RP VARIANTS CYS-38; HIS-47 AND MET-66, AND MUTAGENESIS OF CYS-36 AND CYS-60. RX PubMed=24990881; DOI=10.1126/scitranslmed.3009093; RA Kleinberger G., Yamanishi Y., Suarez-Calvet M., Czirr E., Lohmann E., RA Cuyvers E., Struyfs H., Pettkus N., Wenninger-Weinzierl A., Mazaheri F., RA Tahirovic S., Lleo A., Alcolea D., Fortea J., Willem M., Lammich S., RA Molinuevo J.L., Sanchez-Valle R., Antonell A., Ramirez A., Heneka M.T., RA Sleegers K., van der Zee J., Martin J.J., Engelborghs S., RA Demirtas-Tatlidede A., Zetterberg H., Van Broeckhoven C., Gurvit H., RA Wyss-Coray T., Hardy J., Colonna M., Haass C.; RT "TREM2 mutations implicated in neurodegeneration impair cell surface RT transport and phagocytosis."; RL Sci. Transl. Med. 6:243RA86-243RA86(2014). RN [13] RP SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT AD17 HIS-47, RP CHARACTERIZATION OF VARIANTS PHE-16; MET-27; VAL-28; PHE-31; RP 33-GLN--THR-230; CYS-38; CYS-47; MET-66; ASN-87; SER-130; GLN-136; TRP-136; RP LYS-151; TYR-157; ARG-162; THR-196; GLN-215 AND ILE-223, AND VARIANT RP ASP-202 (ISOFORM 2). RX PubMed=27589997; DOI=10.1186/s40478-016-0367-7; RA Sirkis D.W., Bonham L.W., Aparicio R.E., Geier E.G., Ramos E.M., Wang Q., RA Karydas A., Miller Z.A., Miller B.L., Coppola G., Yokoyama J.S.; RT "Rare TREM2 variants associated with Alzheimer's disease display reduced RT cell surface expression."; RL Acta Neuropathol. Commun. 4:98-98(2016). RN [14] RP VARIANTS TYR-157 AND THR-192, AND VARIANTS CYS-183 AND CYS-200 (ISOFORM 2). RX PubMed=27067662; DOI=10.1016/j.neurobiolaging.2016.02.023; RA Jiang T., Tan L., Chen Q., Tan M.S., Zhou J.S., Zhu X.C., Lu H., Wang H.F., RA Zhang Y.D., Yu J.T.; RT "A rare coding variant in TREM2 increases risk for Alzheimer's disease in RT Han Chinese."; RL Neurobiol. Aging 42:E1-E3(2016). RN [15] RP FUNCTION, TISSUE SPECIFICITY, CHARACTERIZATION OF VARIANTS CYS-38; HIS-47; RP HIS-62; MET-66 AND ASN-87, AND MUTAGENESIS OF LYS-48. RX PubMed=27477018; DOI=10.1016/j.neuron.2016.06.015; RA Yeh F.L., Wang Y., Tom I., Gonzalez L.C., Sheng M.; RT "TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby RT Facilitates Uptake of Amyloid-Beta by Microglia."; RL Neuron 91:328-340(2016). RN [16] RP TISSUE SPECIFICITY, AND CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62. RX PubMed=28802038; DOI=10.1016/j.cell.2017.07.023; RA Ulland T.K., Song W.M., Huang S.C., Ulrich J.D., Sergushichev A., RA Beatty W.L., Loboda A.A., Zhou Y., Cairns N.J., Kambal A., Loginicheva E., RA Gilfillan S., Cella M., Virgin H.W., Unanue E.R., Wang Y., Artyomov M.N., RA Holtzman D.M., Colonna M.; RT "TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease."; RL Cell 170:649-663(2017). RN [17] RP SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND CHARACTERIZATION OF RP VARIANT TYR-157. RX PubMed=28855300; DOI=10.15252/emmm.201707672; RA Schlepckow K., Kleinberger G., Fukumori A., Feederle R., RA Lichtenthaler S.F., Steiner H., Haass C.; RT "An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and RT affects shedding and phagocytic function."; RL EMBO Mol. Med. 9:1356-1365(2017). RN [18] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, PROTEOLYTIC PROCESSING, AND RP CHARACTERIZATION OF VARIANT TYR-157. RX PubMed=28855301; DOI=10.15252/emmm.201707673; RA Thornton P., Sevalle J., Deery M.J., Fraser G., Zhou Y., Staahl S., RA Franssen E.H., Dodd R.B., Qamar S., Gomez Perez-Nievas B., Nicol L.S., RA Eketjaell S., Revell J., Jones C., Billinton A., St George-Hyslop P.H., RA Chessell I., Crowther D.C.; RT "TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the RT Alzheimer's disease-associated H157Y variant."; RL EMBO Mol. Med. 9:1366-1378(2017). RN [19] RP SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS CYS-38 AND MET-66, AND RP CHARACTERIZATION OF VARIANTS PLOSL2 GLY-126; GLY-134 AND ASN-186. RX PubMed=28768830; DOI=10.1091/mbc.e17-06-0423; RA Sirkis D.W., Aparicio R.E., Schekman R.; RT "Neurodegeneration-associated mutant TREM2 proteins abortively cycle RT between the ER and ER-Golgi intermediate compartment."; RL Mol. Biol. Cell 28:2723-2733(2017). RN [20] RP SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND CHARACTERIZATION OF RP VARIANT HIS-47. RX PubMed=28923481; DOI=10.1016/j.neulet.2017.09.034; RA Feuerbach D., Schindler P., Barske C., Joller S., Beng-Louka E., RA Worringer K.A., Kommineni S., Kaykas A., Ho D.J., Ye C., Welzenbach K., RA Elain G., Klein L., Brzak I., Mir A.K., Farady C.J., Aichholz R., Popp S., RA George N., Neumann U.; RT "ADAM17 is the main sheddase for the generation of human triggering RT receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 RT after Histidine 157."; RL Neurosci. Lett. 660:109-114(2017). RN [21] RP CHARACTERIZATION OF VARIANT HIS-47. RX PubMed=30442540; DOI=10.1016/j.jalz.2018.09.006; RA Claes C., Van Den Daele J., Boon R., Schouteden S., Colombo A., RA Monasor L.S., Fiers M., Ordovas L., Nami F., Bohrmann B., Tahirovic S., RA De Strooper B., Verfaillie C.M.; RT "Human stem cell-derived monocytes and microglia-like cells reveal impaired RT amyloid plaque clearance upon heterozygous or homozygous loss of TREM2."; RL Alzheimers Dement. 15:453-464(2018). RN [22] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=29752066; DOI=10.1016/j.immuni.2018.04.016; RA Filipello F., Morini R., Corradini I., Zerbi V., Canzi A., Michalski B., RA Erreni M., Markicevic M., Starvaggi-Cucuzza C., Otero K., Piccio L., RA Cignarella F., Perrucci F., Tamborini M., Genua M., Rajendran L., Menna E., RA Vetrano S., Fahnestock M., Paolicelli R.C., Matteoli M.; RT "The Microglial Innate Immune Receptor TREM2 Is Required for Synapse RT Elimination and Normal Brain Connectivity."; RL Immunity 48:979-991(2018). RN [23] RP FUNCTION, AND CHARACTERIZATION OF VARIANTS HIS-47 AND HIS-62. RX PubMed=29518356; DOI=10.1016/j.neuron.2018.01.031; RA Zhao Y., Wu X., Li X., Jiang L.L., Gui X., Liu Y., Sun Y., Zhu B., RA Pina-Crespo J.C., Zhang M., Zhang N., Chen X., Bu G., An Z., Huang T.Y., RA Xu H.; RT "TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function."; RL Neuron 97:1023-1031(2018). RN [24] {ECO:0007744|PDB:5ELI} RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 19-133, DISULFIDE BONDS, SUBUNIT, RP SUBCELLULAR LOCATION, MUTAGENESIS OF ASN-68; ARG-76 AND ARG-77, RP GLYCOSYLATION AT ASN-79, CHARACTERIZATION OF VARIANTS CYS-38; HIS-47; RP HIS-62; MET-66; ASN-87 AND LYS-96, AND CHARACTERIZATION OF VARIANT PLOSL2 RP GLY-126. RX PubMed=27995897; DOI=10.7554/elife.20391; RA Kober D.L., Alexander-Brett J.M., Karch C.M., Cruchaga C., Colonna M., RA Holtzman M.J., Brett T.J.; RT "Neurodegenerative disease mutations in TREM2 reveal a functional surface RT and distinct loss-of-function mechanisms."; RL Elife 5:E20391-E20391(2016). RN [25] {ECO:0007744|PDB:6B8O} RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 19-174 IN COMPLEX WITH RP PHOSPHATIDYLSERINE, PHOSPHOLIPID-BINDING, DISULFIDE BONDS, FUNCTION, RP SUBUNIT, GLYCOSYLATION AT ASN-20 AND ASN-79, CHARACTERIZATION OF VARIANT RP HIS-47, AND MUTAGENESIS OF ASN-20. RX PubMed=29794134; DOI=10.1074/jbc.ra118.002352; RA Sudom A., Talreja S., Danao J., Bragg E., Kegel R., Min X., Richardson J., RA Zhang Z., Sharkov N., Marcora E., Thibault S., Bradley J., Wood S., RA Lim A.C., Chen H., Wang S., Foltz I.N., Sambashivan S., Wang Z.; RT "Molecular basis for the loss-of-function effects of the Alzheimer's RT disease-associated R47H variant of the immune receptor TREM2."; RL J. Biol. Chem. 293:12634-12646(2018). RN [26] RP INVOLVEMENT IN PLOSL2, AND VARIANT PLOSL2 33-GLN--THR-230 DEL. RX PubMed=12754369; DOI=10.1136/jnnp.74.6.825-a; RA Soragna D., Papi L., Ratti M.T., Sestini R., Tupler R., Montalbetti L.; RT "An Italian family affected by Nasu-Hakola disease with a novel genetic RT mutation in the TREM2 gene."; RL J. Neurol. Neurosurg. Psych. 74:825-826(2003). RN [27] RP INVOLVEMENT IN PLOSL2, AND VARIANT PLOSL2 33-GLN--THR-230 DEL. RX PubMed=23399524; DOI=10.1016/j.jns.2013.01.021; RA Bock V., Botturi A., Gaviani P., Lamperti E., Maccagnano C., Piccio L., RA Silvani A., Salmaggi A.; RT "Polycystic Lipomembranous Osteodysplasia with Sclerosing RT Leukoencephalopathy (PLOSL): a new report of an Italian woman and review of RT the literature."; RL J. Neurol. Sci. 326:115-119(2013). RN [28] RP CHARACTERIZATION OF VARIANT PLOSL2 33-GLN--THR-230 DEL, CHARACTERIZATION OF RP VARIANTS CYS-38; HIS-47 AND MET-66, AND SUBCELLULAR LOCATION. RX PubMed=25615530; DOI=10.1111/tra.12264; RA Park J.S., Ji I.J., An H.J., Kang M.J., Kang S.W., Kim D.H., Yoon S.Y.; RT "Disease-associated mutations of TREM2 alter the processing of N-linked RT oligosaccharides in the Golgi apparatus."; RL Traffic 16:510-518(2015). RN [29] RP VARIANT PLOSL2 33-GLN--THR-230 DEL. RX PubMed=29142083; DOI=10.1212/wnl.0000000000004747; RA Ghezzi L., Carandini T., Arighi A., Fenoglio C., Arcaro M., De Riz M., RA Pietroboni A.M., Fumagalli G.G., Basilico P., Calvi A., Scarioni M., RA Colombi A., Serpente M., Marotta G., Benti R., Scarpini E., Galimberti D.; RT "Evidence of CNS beta-amyloid deposition in Nasu-Hakola disease due to the RT TREM2 Q33X mutation."; RL Neurology 89:2503-2505(2017). RN [30] RP INVOLVEMENT IN AD17, AND VARIANT AD17 HIS-47. RX PubMed=23150908; DOI=10.1056/nejmoa1211103; RA Jonsson T., Stefansson H., Steinberg S., Jonsdottir I., Jonsson P.V., RA Snaedal J., Bjornsson S., Huttenlocher J., Levey A.I., Lah J.J., RA Rujescu D., Hampel H., Giegling I., Andreassen O.A., Engedal K., RA Ulstein I., Djurovic S., Ibrahim-Verbaas C., Hofman A., Ikram M.A., RA van Duijn C.M., Thorsteinsdottir U., Kong A., Stefansson K.; RT "Variant of TREM2 associated with the risk of Alzheimer's disease."; RL N. Engl. J. Med. 368:107-116(2013). RN [31] RP INVOLVEMENT IN AD17, VARIANTS AD17 HIS-47 AND HIS-62, VARIANTS RP 33-GLN--THR-230 DEL; HIS-52; MET-66; ASN-87; LYS-96; TRP-136; GLN-136; RP LYS-151; TYR-157; PRO-211; GLN-215 AND ILE-223, AND VARIANTS RP 191-TRP--THR-230 DEL AND ASP-202 (ISOFORM 2). RX PubMed=24899047; DOI=10.1093/hmg/ddu277; RA Jin S.C., Benitez B.A., Karch C.M., Cooper B., Skorupa T., Carrell D., RA Norton J.B., Hsu S., Harari O., Cai Y., Bertelsen S., Goate A.M., RA Cruchaga C.; RT "Coding variants in TREM2 increase risk for Alzheimer's disease."; RL Hum. Mol. Genet. 23:5838-5846(2014). RN [32] RP INVOLVEMENT IN AD17, AND VARIANTS AD17 HIS-47 AND HIS-62. RX PubMed=38899702; DOI=10.1056/nejmc2314334; RA Stefansson H., Walters G.B., Sveinbjornsson G., Tragante V., Einarsson G., RA Helgason H., Sigurdsson A., Beyter D., Snaebjarnarson A.S., RA Ivarsdottir E.V., Thorleifsson G., Halldorsson B.V., Norddahl G., RA Styrkarsdottir U., Sturluson A., Holm H., Helgason A., Moore K., RA Eggertsson H.P., Oddsson A.H., Jonsdottir G.A., Gunnarsson A.F., RA Bjornsdottir G., Gisladottir R.S., Thorgeirsson T.E., Skuladottir A., RA Gudbjartsson D.F., Sulem P., Jonsson P., Thordardottir S., Snaedal J., RA Eyjolfsdottir H., Creese B., Ballard C., Corbett A., RA Vasconcelos Da Silva M., Aarsland D., Andreassen O.A., Selbaek G., RA Djurovic S., Stordal E., Fladby T., Haavik J., Igland J., Giil L.M., RA Eriksson S., Hallmans G., Loevheim H., Lopatko Lindman K., Trupp M., RA Forsgren L., Werge T., Banasik K., Brunak S., Ullum H., Frikke-Schmidt R., RA Ostrowski S.R., Didriksen M., Soerensen E., Simonsen A.H., Nielsen J.E., RA Waldemar G., Pedersen O.B., Erikstrup C., Knowlton K.U., Nadauld L.D., RA Stefansson K.; RT "Homozygosity for R47H in TREM2 and the Risk of Alzheimer's Disease."; RL N. Engl. J. Med. 390:2217-2219(2024). CC -!- FUNCTION: Forms a receptor signaling complex with TYROBP which mediates CC signaling and cell activation following ligand binding CC (PubMed:10799849). Acts as a receptor for amyloid-beta protein 42, a CC cleavage product of the amyloid-beta precursor protein APP, and CC mediates its uptake and degradation by microglia (PubMed:27477018, CC PubMed:29518356). Binding to amyloid-beta 42 mediates microglial CC activation, proliferation, migration, apoptosis and expression of pro- CC inflammatory cytokines, such as IL6R and CCL3, and the anti- CC inflammatory cytokine ARG1 (By similarity). Acts as a receptor for CC lipoprotein particles such as LDL, VLDL, and HDL and for CC apolipoproteins such as APOA1, APOA2, APOB, APOE, APOE2, APOE3, APOE4, CC and CLU and enhances their uptake in microglia (PubMed:27477018). Binds CC phospholipids (preferably anionic lipids) such as phosphatidylserine, CC phosphatidylethanolamine, phosphatidylglycerol and sphingomyelin CC (PubMed:29794134). Regulates microglial proliferation by acting as an CC upstream regulator of the Wnt/beta-catenin signaling cascade (By CC similarity). Required for microglial phagocytosis of apoptotic neurons CC (PubMed:24990881). Also required for microglial activation and CC phagocytosis of myelin debris after neuronal injury and of neuronal CC synapses during synapse elimination in the developing brain (By CC similarity). Regulates microglial chemotaxis and process outgrowth, and CC also the microglial response to oxidative stress and lipopolysaccharide CC (By similarity). It suppresses PI3K and NF-kappa-B signaling in CC response to lipopolysaccharide; thus promoting phagocytosis, CC suppressing pro-inflammatory cytokine and nitric oxide production, CC inhibiting apoptosis and increasing expression of IL10 and TGFB (By CC similarity). During oxidative stress, it promotes anti-apoptotic NF- CC kappa-B signaling and ERK signaling (By similarity). Plays a role in CC microglial MTOR activation and metabolism (By similarity). Regulates CC age-related changes in microglial numbers (PubMed:29752066). Triggers CC activation of the immune responses in macrophages and dendritic cells CC (PubMed:10799849). Mediates cytokine-induced formation of CC multinucleated giant cells which are formed by the fusion of CC macrophages (By similarity). In dendritic cells, receptor of SEMA6D CC with PLEXNA1 as coreceptor and mediates up-regulation of chemokine CC receptor CCR7 and dendritic cell maturation and survival CC (PubMed:11602640). Involved in the positive regulation of osteoclast CC differentiation (PubMed:12925681). {ECO:0000250|UniProtKB:Q99NH8, CC ECO:0000269|PubMed:10799849, ECO:0000269|PubMed:11602640, CC ECO:0000269|PubMed:12925681, ECO:0000269|PubMed:24990881, CC ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:29518356, CC ECO:0000269|PubMed:29752066, ECO:0000269|PubMed:29794134}. CC -!- SUBUNIT: Monomer (PubMed:27995897). After ectodomain shedding, the CC extracellular domain oligomerizes, which is enhanced and stabilized by CC binding of phosphatidylserine (PubMed:29794134). Interacts with CC TYROBP/DAP12 (PubMed:11602640, PubMed:25957402). Interaction with CC TYROBP is required for stabilization of the TREM2 C-terminal fragment CC (TREM2-CTF) which is produced by proteolytic processing CC (PubMed:25957402). Interacts with PLXNA1 (via TIG domains); the CC interaction mediates SEMA6D binding and signaling through TYROBP (By CC similarity). {ECO:0000250|UniProtKB:Q99NH8, CC ECO:0000269|PubMed:11602640, ECO:0000269|PubMed:25957402, CC ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:29794134}. CC -!- INTERACTION: CC Q9NZC2; P02649: APOE; NbExp=4; IntAct=EBI-14036387, EBI-1222467; CC Q9NZC2; PRO_0000000092 [P05067]: APP; NbExp=4; IntAct=EBI-14036387, EBI-821758; CC Q9NZC2; P49768: PSEN1; NbExp=5; IntAct=EBI-14036387, EBI-297277; CC Q9NZC2; O43914: TYROBP; NbExp=4; IntAct=EBI-14036387, EBI-2214794; CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane CC {ECO:0000269|PubMed:24078628, ECO:0000269|PubMed:24990881, CC ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27589997, CC ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830, CC ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301, CC ECO:0000269|PubMed:28923481}; Single-pass type I membrane protein CC {ECO:0000255}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Secreted {ECO:0000305}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Secreted {ECO:0000305}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9NZC2-1; Sequence=Displayed; CC Name=2; Synonyms=TREM-2V; CC IsoId=Q9NZC2-2; Sequence=VSP_010792; CC Name=3; CC IsoId=Q9NZC2-3; Sequence=VSP_010793; CC -!- TISSUE SPECIFICITY: Expressed in the brain, specifically in microglia CC and in the fusiform gyrus (at protein level) (PubMed:27477018, CC PubMed:28802038, PubMed:28855300, PubMed:29752066). Expressed on CC macrophages and dendritic cells but not on granulocytes or monocytes CC (PubMed:10799849, PubMed:28855301). In the CNS strongest expression CC seen in the basal ganglia, corpus callosum, medulla oblongata and CC spinal cord (PubMed:12080485). {ECO:0000269|PubMed:10799849, CC ECO:0000269|PubMed:12080485, ECO:0000269|PubMed:27477018, CC ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:28855300, CC ECO:0000269|PubMed:28855301, ECO:0000269|PubMed:29752066}. CC -!- PTM: Undergoes ectodomain shedding through proteolytic cleavage by CC ADAM10 and ADAM17 to produce a transmembrane segment, the TREM2 C- CC terminal fragment (TREM2-CTF), which is subsequently cleaved by gamma- CC secretase. {ECO:0000269|PubMed:24078628, ECO:0000269|PubMed:24990881, CC ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301, CC ECO:0000269|PubMed:28923481}. CC -!- DISEASE: Polycystic lipomembranous osteodysplasia with sclerosing CC leukoencephalopathy 2 (PLOSL2) [MIM:618193]: An autosomal recessive CC disease characterized by presenile frontal dementia with CC leukoencephalopathy and basal ganglia calcification. In most cases the CC disorder first manifests in early adulthood as pain and swelling in CC ankles and feet, followed by bone fractures. Neurologic symptoms CC manifest in the fourth decade of life as a frontal lobe syndrome with CC loss of judgment, euphoria, and disinhibition. Progressive decline in CC other cognitive domains begins to develop at about the same time. The CC disorder culminates in a profound dementia and death by age 50 years. CC {ECO:0000269|PubMed:12080485, ECO:0000269|PubMed:12754369, CC ECO:0000269|PubMed:12925681, ECO:0000269|PubMed:15883308, CC ECO:0000269|PubMed:23399524, ECO:0000269|PubMed:25615530, CC ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830, CC ECO:0000269|PubMed:28923481, ECO:0000269|PubMed:29142083}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Alzheimer disease 17 (AD17) [MIM:615080]: A late-onset form of CC Alzheimer disease. Alzheimer disease is a neurodegenerative disorder CC characterized by progressive dementia, loss of cognitive abilities, and CC deposition of fibrillar amyloid proteins as intraneuronal CC neurofibrillary tangles, extracellular amyloid plaques and vascular CC amyloid deposits. The major constituents of these plaques are CC neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that CC are produced by the proteolysis of the transmembrane APP protein. The CC cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, CC such as C31, are also implicated in neuronal death. CC {ECO:0000269|PubMed:23150908, ECO:0000269|PubMed:24899047, CC ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:38899702}. Note=Disease CC susceptibility is associated with variants affecting the gene CC represented in this entry. CC -!- SEQUENCE CAUTION: CC Sequence=BAB78736.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF213457; AAF69824.1; -; mRNA. DR EMBL; AB062787; BAB78736.1; ALT_INIT; mRNA. DR EMBL; BC032362; AAH32362.1; -; mRNA. DR CCDS; CCDS4852.1; -. [Q9NZC2-1] DR CCDS; CCDS64422.1; -. [Q9NZC2-2] DR RefSeq; NP_001258750.1; NM_001271821.2. [Q9NZC2-2] DR RefSeq; NP_061838.1; NM_018965.4. [Q9NZC2-1] DR PDB; 5ELI; X-ray; 3.10 A; A/B=19-133. DR PDB; 5UD7; X-ray; 2.20 A; A/B/C/D/E/F=19-174. DR PDB; 5UD8; X-ray; 1.80 A; A/B=19-130. DR PDB; 6B8O; X-ray; 2.20 A; A/B/C/D/E/F=19-174. DR PDB; 6XDS; X-ray; 1.47 A; A=18-135. DR PDB; 6Y6C; X-ray; 2.26 A; A/B=19-174. DR PDB; 6YMQ; X-ray; 3.07 A; D000/G/H/I/J/K=19-131. DR PDB; 6YYE; X-ray; 3.36 A; A/B=19-131. DR PDB; 6Z0G; NMR; -; A=161-206. DR PDB; 6Z0H; NMR; -; A=161-206. DR PDB; 6Z0I; NMR; -; A=161-206. DR PDB; 8T51; X-ray; 1.90 A; E/F=148-166. DR PDB; 8T59; X-ray; 2.00 A; E/F=148-166. DR PDB; 9PWN; X-ray; 1.80 A; A=131-148. DR PDB; 9PX5; X-ray; 3.70 A; A=18-135. DR PDBsum; 5ELI; -. DR PDBsum; 5UD7; -. DR PDBsum; 5UD8; -. DR PDBsum; 6B8O; -. DR PDBsum; 6XDS; -. DR PDBsum; 6Y6C; -. DR PDBsum; 6YMQ; -. DR PDBsum; 6YYE; -. DR PDBsum; 6Z0G; -. DR PDBsum; 6Z0H; -. DR PDBsum; 6Z0I; -. DR PDBsum; 8T51; -. DR PDBsum; 8T59; -. DR PDBsum; 9PWN; -. DR PDBsum; 9PX5; -. DR AlphaFoldDB; Q9NZC2; -. DR SMR; Q9NZC2; -. DR BioGRID; 119925; 25. DR FunCoup; Q9NZC2; 306. DR IntAct; Q9NZC2; 9. DR STRING; 9606.ENSP00000362205; -. DR TCDB; 8.A.218.1.1; the triggering receptor expressed on myeloid cells 2 (trem2) family. DR GlyCosmos; Q9NZC2; 2 sites, No reported glycans. DR GlyGen; Q9NZC2; 2 sites. DR iPTMnet; Q9NZC2; -. DR PhosphoSitePlus; Q9NZC2; -. DR BioMuta; TREM2; -. DR DMDM; 50401689; -. DR MassIVE; Q9NZC2; -. DR PaxDb; 9606-ENSP00000362205; -. DR PeptideAtlas; Q9NZC2; -. DR ProteomicsDB; 83358; -. [Q9NZC2-1] DR ProteomicsDB; 83359; -. [Q9NZC2-2] DR ProteomicsDB; 83360; -. [Q9NZC2-3] DR ABCD; Q9NZC2; 4 sequenced antibodies. DR Antibodypedia; 2280; 739 antibodies from 39 providers. DR DNASU; 54209; -. DR Ensembl; ENST00000338469.3; ENSP00000342651.4; ENSG00000095970.18. [Q9NZC2-2] DR Ensembl; ENST00000373113.8; ENSP00000362205.3; ENSG00000095970.18. [Q9NZC2-1] DR Ensembl; ENST00000373122.8; ENSP00000362214.4; ENSG00000095970.18. [Q9NZC2-3] DR GeneID; 54209; -. DR KEGG; hsa:54209; -. DR MANE-Select; ENST00000373113.8; ENSP00000362205.3; NM_018965.4; NP_061838.1. DR UCSC; uc003opy.4; human. [Q9NZC2-1] DR AGR; HGNC:17761; -. DR ClinPGx; PA38468; -. DR CTD; 54209; -. DR DisGeNET; 54209; -. DR GeneCards; TREM2; -. DR GeneReviews; TREM2; -. DR HGNC; HGNC:17761; TREM2. DR HPA; ENSG00000095970; Tissue enhanced (brain, choroid plexus). DR MalaCards; TREM2; -. DR MIM; 605086; gene. DR MIM; 615080; phenotype. DR MIM; 618193; phenotype. DR NIAGADS; ENSG00000095970; -. DR OpenTargets; ENSG00000095970; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 275864; Behavioral variant of frontotemporal dementia. DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease. DR Orphanet; 2770; Nasu-Hakola disease. DR Orphanet; 100070; Progressive non-fluent aphasia. DR Orphanet; 100069; Semantic dementia. DR VEuPathDB; HostDB:ENSG00000095970; -. DR eggNOG; ENOG502S4HV; Eukaryota. DR GeneTree; ENSGT00470000042297; -. DR HOGENOM; CLU_076120_0_0_1; -. DR InParanoid; Q9NZC2; -. DR OMA; CAPSFRH; -. DR OrthoDB; 9805957at2759; -. DR PAN-GO; Q9NZC2; 8 GO annotations based on evolutionary models. DR PhylomeDB; Q9NZC2; -. DR PathwayCommons; Q9NZC2; -. DR Reactome; R-HSA-198933; Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell. DR Reactome; R-HSA-2172127; DAP12 interactions. DR Reactome; R-HSA-2424491; DAP12 signaling. DR Reactome; R-HSA-416700; Other semaphorin interactions. DR SignaLink; Q9NZC2; -. DR Agora; ENSG00000095970; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 54209; 13 hits in 1137 CRISPR screens. DR ChiTaRS; TREM2; human. DR GeneWiki; TREM2; -. DR GenomeRNAi; 54209; -. DR Pharos; Q9NZC2; Tbio. DR PRO; PR:Q9NZC2; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; Q9NZC2; protein. DR Bgee; ENSG00000095970; Expressed in C1 segment of cervical spinal cord and 133 other cell types or tissues. DR ExpressionAtlas; Q9NZC2; baseline and differential. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0044853; C:plasma membrane raft; IDA:ARUK-UCL. DR GO; GO:0002116; C:semaphorin receptor complex; ISS:UniProt. DR GO; GO:0001540; F:amyloid-beta binding; IPI:ARUK-UCL. DR GO; GO:0034186; F:apolipoprotein A-I binding; IPI:ARUK-UCL. DR GO; GO:0034185; F:apolipoprotein binding; IPI:ARUK-UCL. DR GO; GO:0008013; F:beta-catenin binding; IPI:ARUK-UCL. DR GO; GO:0008035; F:high-density lipoprotein particle binding; IDA:ARUK-UCL. DR GO; GO:0019209; F:kinase activator activity; IMP:ARUK-UCL. DR GO; GO:0008289; F:lipid binding; TAS:ARUK-UCL. DR GO; GO:0001530; F:lipopolysaccharide binding; IEA:Ensembl. DR GO; GO:0071813; F:lipoprotein particle binding; IDA:ARUK-UCL. DR GO; GO:0070891; F:lipoteichoic acid binding; IEA:Ensembl. DR GO; GO:0030169; F:low-density lipoprotein particle binding; IDA:ARUK-UCL. DR GO; GO:0042834; F:peptidoglycan binding; IEA:Ensembl. DR GO; GO:0008429; F:phosphatidylethanolamine binding; IDA:ARUK-UCL. DR GO; GO:0001786; F:phosphatidylserine binding; IDA:ARUK-UCL. DR GO; GO:0005543; F:phospholipid binding; IDA:UniProtKB. DR GO; GO:1990782; F:protein tyrosine kinase binding; ISS:ARUK-UCL. DR GO; GO:0044877; F:protein-containing complex binding; IPI:ARUK-UCL. DR GO; GO:0097110; F:scaffold protein binding; IPI:BHF-UCL. DR GO; GO:0017154; F:semaphorin receptor activity; IEA:Ensembl. DR GO; GO:0030215; F:semaphorin receptor binding; IEA:Ensembl. DR GO; GO:0038023; F:signaling receptor activity; IMP:ARUK-UCL. DR GO; GO:0120146; F:sulfatide binding; IDA:ARUK-UCL. DR GO; GO:0004888; F:transmembrane signaling receptor activity; IDA:UniProt. DR GO; GO:0034189; F:very-low-density lipoprotein particle binding; IDA:ARUK-UCL. DR GO; GO:0097242; P:amyloid-beta clearance; IDA:UniProt. DR GO; GO:0150094; P:amyloid-beta clearance by cellular catabolic process; IMP:ARUK-UCL. DR GO; GO:0043277; P:apoptotic cell clearance; ISS:UniProtKB. DR GO; GO:0048143; P:astrocyte activation; ISS:ARUK-UCL. DR GO; GO:1904646; P:cellular response to amyloid-beta; IDA:UniProt. DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl. DR GO; GO:0071396; P:cellular response to lipid; IMP:ARUK-UCL. DR GO; GO:0071402; P:cellular response to lipoprotein particle stimulus; IDA:UniProt. DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Ensembl. DR GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; IDA:ARUK-UCL. DR GO; GO:0071224; P:cellular response to peptidoglycan; IEA:Ensembl. DR GO; GO:0150062; P:complement-mediated synapse pruning; ISS:ARUK-UCL. DR GO; GO:0038160; P:CXCL12-activated CXCR4 signaling pathway; IMP:ARUK-UCL. DR GO; GO:0050829; P:defense response to Gram-negative bacterium; ISS:ARUK-UCL. DR GO; GO:0097028; P:dendritic cell differentiation; IDA:BHF-UCL. DR GO; GO:0097062; P:dendritic spine maintenance; ISS:ARUK-UCL. DR GO; GO:0032497; P:detection of lipopolysaccharide; IEA:Ensembl. DR GO; GO:0070392; P:detection of lipoteichoic acid; IEA:Ensembl. DR GO; GO:0032499; P:detection of peptidoglycan; IEA:Ensembl. DR GO; GO:1905805; P:excitatory synapse pruning; ISS:ARUK-UCL. DR GO; GO:0006959; P:humoral immune response; TAS:ProtInc. DR GO; GO:0098657; P:import into cell; ISS:ARUK-UCL. DR GO; GO:0055088; P:lipid homeostasis; ISS:ARUK-UCL. DR GO; GO:0007613; P:memory; IDA:ARUK-UCL. DR GO; GO:0001774; P:microglial cell activation; ISS:ARUK-UCL. DR GO; GO:0002282; P:microglial cell activation involved in immune response; ISS:ARUK-UCL. DR GO; GO:0061518; P:microglial cell proliferation; ISS:ARUK-UCL. DR GO; GO:1905907; P:negative regulation of amyloid fibril formation; ISS:ARUK-UCL. DR GO; GO:0061889; P:negative regulation of astrocyte activation; ISS:ARUK-UCL. DR GO; GO:1904093; P:negative regulation of autophagic cell death; ISS:ARUK-UCL. DR GO; GO:0010507; P:negative regulation of autophagy; ISS:ARUK-UCL. DR GO; GO:0043124; P:negative regulation of canonical NF-kappaB signal transduction; ISS:ARUK-UCL. DR GO; GO:0050866; P:negative regulation of cell activation; ISS:ARUK-UCL. DR GO; GO:0010887; P:negative regulation of cholesterol storage; ISS:ARUK-UCL. DR GO; GO:1900016; P:negative regulation of cytokine production involved in inflammatory response; ISS:ARUK-UCL. DR GO; GO:0070345; P:negative regulation of fat cell proliferation; ISS:ARUK-UCL. DR GO; GO:0034351; P:negative regulation of glial cell apoptotic process; ISS:ARUK-UCL. DR GO; GO:0002862; P:negative regulation of inflammatory response to antigenic stimulus; ISS:ARUK-UCL. DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; IEA:Ensembl. DR GO; GO:1902227; P:negative regulation of macrophage colony-stimulating factor signaling pathway; IMP:ARUK-UCL. DR GO; GO:0150079; P:negative regulation of neuroinflammatory response; IMP:ARUK-UCL. DR GO; GO:1900226; P:negative regulation of NLRP3 inflammasome complex assembly; IMP:ARUK-UCL. DR GO; GO:1903753; P:negative regulation of p38MAPK cascade; ISS:ARUK-UCL. DR GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IMP:ARUK-UCL. DR GO; GO:0034136; P:negative regulation of toll-like receptor 2 signaling pathway; ISS:ARUK-UCL. DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; ISS:ARUK-UCL. DR GO; GO:0010891; P:negative regulation of triglyceride storage; ISS:ARUK-UCL. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IEA:Ensembl. DR GO; GO:0030316; P:osteoclast differentiation; IMP:UniProtKB. DR GO; GO:0006911; P:phagocytosis, engulfment; IEA:Ensembl. DR GO; GO:0006910; P:phagocytosis, recognition; IMP:ARUK-UCL. DR GO; GO:1900223; P:positive regulation of amyloid-beta clearance; IMP:ARUK-UCL. DR GO; GO:0002588; P:positive regulation of antigen processing and presentation of peptide antigen via MHC class II; IDA:BHF-UCL. DR GO; GO:2001171; P:positive regulation of ATP biosynthetic process; ISS:ARUK-UCL. DR GO; GO:1903082; P:positive regulation of C-C chemokine receptor CCR7 signaling pathway; IDA:BHF-UCL. DR GO; GO:0050850; P:positive regulation of calcium-mediated signaling; IDA:BHF-UCL. DR GO; GO:1905291; P:positive regulation of CAMKK-AMPK signaling cascade; ISS:ARUK-UCL. DR GO; GO:2000350; P:positive regulation of CD40 signaling pathway; IDA:BHF-UCL. DR GO; GO:0050921; P:positive regulation of chemotaxis; ISS:ARUK-UCL. DR GO; GO:0010875; P:positive regulation of cholesterol efflux; ISS:ARUK-UCL. DR GO; GO:0045960; P:positive regulation of complement activation, classical pathway; ISS:ARUK-UCL. DR GO; GO:1901076; P:positive regulation of engulfment of apoptotic cell; IMP:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:BHF-UCL. DR GO; GO:1904951; P:positive regulation of establishment of protein localization; ISS:ARUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL. DR GO; GO:0010983; P:positive regulation of high-density lipoprotein particle clearance; ISS:ARUK-UCL. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IEA:Ensembl. DR GO; GO:1902533; P:positive regulation of intracellular signal transduction; IDA:ARUK-UCL. DR GO; GO:1905581; P:positive regulation of low-density lipoprotein particle clearance; ISS:ARUK-UCL. DR GO; GO:0034241; P:positive regulation of macrophage fusion; ISS:UniProtKB. DR GO; GO:1903980; P:positive regulation of microglial cell activation; IMP:UniProtKB. DR GO; GO:1904141; P:positive regulation of microglial cell migration; IMP:ARUK-UCL. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IEA:Ensembl. DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl. DR GO; GO:0050766; P:positive regulation of phagocytosis; IMP:ARUK-UCL. DR GO; GO:0060100; P:positive regulation of phagocytosis, engulfment; IMP:UniProtKB. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:ARUK-UCL. DR GO; GO:0043268; P:positive regulation of potassium ion transport; ISS:ARUK-UCL. DR GO; GO:1901800; P:positive regulation of proteasomal protein catabolic process; ISS:ARUK-UCL. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IDA:BHF-UCL. DR GO; GO:0050714; P:positive regulation of protein secretion; IMP:UniProtKB. DR GO; GO:1905808; P:positive regulation of synapse pruning; IMP:ARUK-UCL. DR GO; GO:0032008; P:positive regulation of TOR signaling; ISS:ARUK-UCL. DR GO; GO:0070269; P:pyroptotic inflammatory response; ISS:ARUK-UCL. DR GO; GO:1900015; P:regulation of cytokine production involved in inflammatory response; ISS:ARUK-UCL. DR GO; GO:0010468; P:regulation of gene expression; ISS:ARUK-UCL. DR GO; GO:0110089; P:regulation of hippocampal neuron apoptotic process; ISS:ARUK-UCL. DR GO; GO:0045088; P:regulation of innate immune response; ISS:ARUK-UCL. DR GO; GO:0032675; P:regulation of interleukin-6 production; ISS:ARUK-UCL. DR GO; GO:0019216; P:regulation of lipid metabolic process; IMP:ARUK-UCL. DR GO; GO:0071640; P:regulation of macrophage inflammatory protein 1 alpha production; ISS:ARUK-UCL. DR GO; GO:1903376; P:regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway; ISS:ARUK-UCL. DR GO; GO:0120035; P:regulation of plasma membrane bounded cell projection organization; IGI:ARUK-UCL. DR GO; GO:0060075; P:regulation of resting membrane potential; ISS:ARUK-UCL. DR GO; GO:0034151; P:regulation of toll-like receptor 6 signaling pathway; ISS:ARUK-UCL. DR GO; GO:0032006; P:regulation of TOR signaling; ISS:ARUK-UCL. DR GO; GO:0045728; P:respiratory burst after phagocytosis; ISS:ARUK-UCL. DR GO; GO:0048678; P:response to axon injury; IMP:ARUK-UCL. DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl. DR GO; GO:0007165; P:signal transduction; IBA:GO_Central. DR GO; GO:0035176; P:social behavior; IMP:ARUK-UCL. DR GO; GO:0002291; P:T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell; IEA:Ensembl. DR DisProt; DP04132; -. DR FunFam; 2.60.40.10:FF:001076; Triggering receptor expressed on myeloid cells 2; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 1. DR InterPro; IPR036179; Ig-like_dom_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR013106; Ig_V-set. DR InterPro; IPR052314; Immune_rcpt_domain. DR PANTHER; PTHR16423:SF11; IG-LIKE DOMAIN-CONTAINING PROTEIN; 1. DR PANTHER; PTHR16423; TREM-LIKE TRANSCRIPT PROTEIN; 1. DR Pfam; PF07686; V-set; 1. DR SUPFAM; SSF48726; Immunoglobulin; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis; KW Cell membrane; Disease variant; Disulfide bond; Glycoprotein; KW Immunoglobulin domain; Lipid-binding; Membrane; Neurodegeneration; KW Proteomics identification; Receptor; Reference proteome; Secreted; Signal; KW Transmembrane; Transmembrane helix. FT SIGNAL 1..18 FT /evidence="ECO:0000255" FT CHAIN 19..230 FT /note="Triggering receptor expressed on myeloid cells 2" FT /id="PRO_0000014987" FT TOPO_DOM 19..174 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 175..195 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 196..230 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 29..112 FT /note="Ig-like V-type" FT BINDING 67 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine" FT /ligand_id="ChEBI:CHEBI:57262" FT /evidence="ECO:0000269|PubMed:29794134, FT ECO:0007744|PDB:6B8O" FT BINDING 68 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine" FT /ligand_id="ChEBI:CHEBI:57262" FT /evidence="ECO:0000269|PubMed:29794134, FT ECO:0007744|PDB:6B8O" FT BINDING 77 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine" FT /ligand_id="ChEBI:CHEBI:57262" FT /evidence="ECO:0000269|PubMed:29794134, FT ECO:0007744|PDB:6B8O" FT BINDING 88 FT /ligand="a 1,2-diacyl-sn-glycero-3-phospho-L-serine" FT /ligand_id="ChEBI:CHEBI:57262" FT /evidence="ECO:0000269|PubMed:29794134, FT ECO:0007744|PDB:6B8O" FT SITE 157..158 FT /note="Cleavage of ectodomain" FT /evidence="ECO:0000269|PubMed:28855300, FT ECO:0000269|PubMed:28855301, ECO:0000269|PubMed:28923481" FT CARBOHYD 20 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:29794134, FT ECO:0007744|PDB:6B8O" FT CARBOHYD 79 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI, FT ECO:0007744|PDB:6B8O" FT DISULFID 36..110 FT /evidence="ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI, FT ECO:0007744|PDB:5UD7, ECO:0007744|PDB:5UD8, FT ECO:0007744|PDB:6B8O" FT DISULFID 51..60 FT /evidence="ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:29794134, ECO:0007744|PDB:5ELI, FT ECO:0007744|PDB:5UD8, ECO:0007744|PDB:6B8O" FT VAR_SEQ 162..230 FT /note="SLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDC FT GHDPGYQLQTLPGLRDT -> AERHVKEDDGRKSPGEVPPGTSPACILATWPPGLLVLL FT WQETTLPEHCFSWTLEAGTG (in isoform 2)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_010792" FT VAR_SEQ 162..230 FT /note="SLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDC FT GHDPGYQLQTLPGLRDT -> PSQGSHLPSCLSKEPLGRRNPLPTHFHPSPPGLHLSHQ FT DSSSQRPLGCSLAWTEARDTSTQ (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_010793" FT VARIANT 14..230 FT /note="Missing (in PLOSL2; results in decreased osteoclast FT differentiation; no TREM2 transcripts can be detected in FT patient cells homozygous for the variant)" FT /evidence="ECO:0000269|PubMed:12925681" FT /id="VAR_081676" FT VARIANT 16 FT /note="S -> F (in dbSNP:rs777808487)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_090043" FT VARIANT 27 FT /note="V -> M (no effect on cell membrane localization; FT dbSNP:rs768745050)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081812" FT VARIANT 28 FT /note="A -> V (increases cell membrane localization; FT dbSNP:rs2234252)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081813" FT VARIANT 31 FT /note="S -> F (decreases cell membrane localization; FT dbSNP:rs746216516)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081814" FT VARIANT 33..230 FT /note="Missing (in PLOSL2; complete loss of protein FT expression)" FT /evidence="ECO:0000269|PubMed:12754369, FT ECO:0000269|PubMed:15883308, ECO:0000269|PubMed:23399524, FT ECO:0000269|PubMed:24899047, ECO:0000269|PubMed:25615530, FT ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:29142083" FT /id="VAR_081677" FT VARIANT 38 FT /note="Y -> C (results in defective protein maturation and FT trafficking; loss of proteolytic cleavage by ADAM10 and FT ectodomain shedding; increases protein aggregation; FT decreases cell membrane localization; decreased FT phagocytosis; loss of LDL, CLU and APOE binding; greatly FT decreases LDL and CLU uptake into cells; FT dbSNP:rs797044603)" FT /evidence="ECO:0000269|PubMed:24990881, FT ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27477018, FT ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:28768830" FT /id="VAR_081815" FT VARIANT 44..230 FT /note="Missing (in PLOSL2)" FT /evidence="ECO:0000269|PubMed:12080485" FT /id="VAR_081678" FT VARIANT 47 FT /note="R -> C (decreased cell surface expression; FT dbSNP:rs753325601)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081816" FT VARIANT 47 FT /note="R -> H (likely risk factor for AD17; no effect on FT cell membrane localization; no effect on autophagy in FT microglia; no effect on phagocytosis, including amyloid FT plaque clearance by microglia; reduces ectodomain shedding FT caused by proteolytic cleavage by ADAM10, while also FT reducing the oligomerization of the extracellular domain FT after shedding; decreases binding to and uptake of LDL and FT CLU into cells; decreases binding to APOE, phospholipids FT and oligomeric APP cleavage product beta-amyloid peptide FT 42; dbSNP:rs75932628)" FT /evidence="ECO:0000269|PubMed:23150908, FT ECO:0000269|PubMed:24899047, ECO:0000269|PubMed:24990881, FT ECO:0000269|PubMed:25615530, ECO:0000269|PubMed:27477018, FT ECO:0000269|PubMed:27589997, ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:28923481, FT ECO:0000269|PubMed:29518356, ECO:0000269|PubMed:29794134, FT ECO:0000269|PubMed:30442540, ECO:0000269|PubMed:38899702" FT /id="VAR_081817" FT VARIANT 52 FT /note="R -> H (in dbSNP:rs374851046)" FT /evidence="ECO:0000269|PubMed:24899047" FT /id="VAR_090044" FT VARIANT 62 FT /note="R -> H (likely risk factor for AD17; does not affect FT protein structure; no effect on cell membrane localization; FT increases autophagy in microglia; decreases LDL, CLU and FT APOE binding; decreases LDL uptake into cells; no effect on FT CLU uptake into cells; decreases the uptake of APP-LDL FT complex in macrophages; decreases binding to oligomeric APP FT cleavage product beta-amyloid peptide 42; FT dbSNP:rs143332484)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:27995897, FT ECO:0000269|PubMed:28802038, ECO:0000269|PubMed:29518356, FT ECO:0000269|PubMed:38899702" FT /id="VAR_081818" FT VARIANT 66 FT /note="T -> M (results in defective protein maturation and FT trafficking; loss of proteolytic cleavage by ADAM10 and FT ectodomain shedding; increases protein aggregation; FT decreases cell membrane localization; decreases FT phagocytosis; loss of LDL, CLU and APOE binding; greatly FT decreases LDL and CLU uptake into cells; FT dbSNP:rs201258663)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:24990881, ECO:0000269|PubMed:25615530, FT ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:27589997, FT ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830" FT /id="VAR_081819" FT VARIANT 78..230 FT /note="Missing (in PLOSL2)" FT /evidence="ECO:0000269|PubMed:12080485" FT /id="VAR_081679" FT VARIANT 87 FT /note="D -> N (decreases LDL, CLU and APOE binding; FT decreases LDL and CLU uptake into cells; no effect on cell FT membrane localization; dbSNP:rs142232675)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27477018, ECO:0000269|PubMed:27589997, FT ECO:0000269|PubMed:27995897" FT /id="VAR_081820" FT VARIANT 96 FT /note="T -> K (does not change protein structure; changes FT protein stability; increases binding to THP-1 cells; FT dbSNP:rs2234253)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27995897" FT /id="VAR_061329" FT VARIANT 96 FT /note="T -> R (in dbSNP:rs2234253)" FT /id="VAR_061330" FT VARIANT 126 FT /note="V -> G (in PLOSL2; results in defective protein FT maturation; increases protein aggregation; decreases cell FT membrane localization; dbSNP:rs121908402)" FT /evidence="ECO:0000269|PubMed:15883308, FT ECO:0000269|PubMed:27995897, ECO:0000269|PubMed:28768830" FT /id="VAR_081680" FT VARIANT 130 FT /note="A -> S (no effect on protein expression and FT maturation; dbSNP:rs759576705)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081821" FT VARIANT 134 FT /note="D -> G (in PLOSL2; uncertain significance; decreased FT protein level; dbSNP:rs28939079)" FT /evidence="ECO:0000269|PubMed:12080485, FT ECO:0000269|PubMed:28768830" FT /id="VAR_019334" FT VARIANT 136 FT /note="R -> Q (slightly decreases cell membrane FT localization; dbSNP:rs149622783)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_081822" FT VARIANT 136 FT /note="R -> W (decreases cell membrane localization; FT dbSNP:rs772641807)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_081823" FT VARIANT 151 FT /note="E -> K (decreases cell membrane localization; FT dbSNP:rs79011726)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_081824" FT VARIANT 157 FT /note="H -> Y (accelerates ectodomain shedding but does not FT alter the cleavage site; decreases cell membrane FT localization; decreases phagocytosis; dbSNP:rs2234255)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27067662, ECO:0000269|PubMed:27589997, FT ECO:0000269|PubMed:28855300, ECO:0000269|PubMed:28855301" FT /id="VAR_033625" FT VARIANT 162 FT /note="S -> R (no effect on protein expression and FT maturation; dbSNP:rs371702633)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_081825" FT VARIANT 186 FT /note="K -> N (in PLOSL2; uncertain significance; increased FT localization at the cell membrane; dbSNP:rs28937876)" FT /evidence="ECO:0000269|PubMed:12080485, FT ECO:0000269|PubMed:28768830" FT /id="VAR_019335" FT VARIANT 192 FT /note="A -> T (in dbSNP:rs150277350)" FT /evidence="ECO:0000269|PubMed:27067662" FT /id="VAR_077696" FT VARIANT 196 FT /note="A -> T (in dbSNP:rs1345120258)" FT /evidence="ECO:0000269|PubMed:27589997" FT /id="VAR_090045" FT VARIANT 211 FT /note="L -> P (in dbSNP:rs2234256)" FT /evidence="ECO:0000269|PubMed:24899047" FT /id="VAR_033626" FT VARIANT 215 FT /note="H -> Q (in dbSNP:rs1161481912)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_090046" FT VARIANT 223 FT /note="T -> I (affects protein maturation; FT dbSNP:rs138355759)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_081826" FT MUTAGEN 20 FT /note="N->D: Loss of glycosylation." FT /evidence="ECO:0000269|PubMed:29794134" FT MUTAGEN 36 FT /note="C->A: Loss of proteolytic cleavage by ADAM10 and FT ectodomain shedding. Decreases protein maturation and cell FT membrane localization." FT /evidence="ECO:0000269|PubMed:24990881" FT MUTAGEN 48 FT /note="K->M: Loss of LDL, CLU and APOE binding." FT /evidence="ECO:0000269|PubMed:27477018" FT MUTAGEN 60 FT /note="C->A: Loss of proteolytic cleavage by ADAM10 and FT ectodomain shedding. Decreases protein maturation and cell FT membrane localization." FT /evidence="ECO:0000269|PubMed:24990881" FT MUTAGEN 68 FT /note="N->K: No effect on cell membrane localization." FT /evidence="ECO:0000269|PubMed:27995897" FT MUTAGEN 76 FT /note="R->D: Decreases binding to THP-1 cells." FT /evidence="ECO:0000269|PubMed:27995897" FT MUTAGEN 77 FT /note="R->D: Decreases binding to THP-1 cells." FT /evidence="ECO:0000269|PubMed:27995897" FT STRAND 19..27 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 32..37 FT /evidence="ECO:0007829|PDB:6XDS" FT TURN 40..45 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 48..53 FT /evidence="ECO:0007829|PDB:6XDS" FT TURN 55..57 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 60..65 FT /evidence="ECO:0007829|PDB:6XDS" FT HELIX 70..72 FT /evidence="ECO:0007829|PDB:6B8O" FT STRAND 74..77 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 80..87 FT /evidence="ECO:0007829|PDB:6XDS" FT TURN 88..91 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 92..99 FT /evidence="ECO:0007829|PDB:6XDS" FT HELIX 102..104 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 106..114 FT /evidence="ECO:0007829|PDB:6XDS" FT STRAND 117..129 FT /evidence="ECO:0007829|PDB:6XDS" FT HELIX 132..135 FT /evidence="ECO:0007829|PDB:6XDS" FT TURN 154..157 FT /evidence="ECO:0007829|PDB:8T51" FT HELIX 159..162 FT /evidence="ECO:0007829|PDB:8T51" FT HELIX 163..165 FT /evidence="ECO:0007829|PDB:6Z0G" FT HELIX 172..189 FT /evidence="ECO:0007829|PDB:6Z0G" FT HELIX 191..198 FT /evidence="ECO:0007829|PDB:6Z0G" FT VARIANT Q9NZC2-2:183 FT /note="S -> C (in dbSNP:rs200820365)" FT /evidence="ECO:0000269|PubMed:27067662" FT /id="VAR_082839" FT VARIANT Q9NZC2-2:191..219 FT /note="Missing" FT /evidence="ECO:0000269|PubMed:24899047" FT /id="VAR_090047" FT VARIANT Q9NZC2-2:200 FT /note="W -> C (in dbSNP:rs1391283629)" FT /evidence="ECO:0000269|PubMed:27067662" FT /id="VAR_082840" FT VARIANT Q9NZC2-2:202 FT /note="E -> D (in dbSNP:rs530314472)" FT /evidence="ECO:0000269|PubMed:24899047, FT ECO:0000269|PubMed:27589997" FT /id="VAR_090048" SQ SEQUENCE 230 AA; 25447 MW; C894AA210F708AF7 CRC64; MEPLRLLILL FVTELSGAHN TTVFQGVAGQ SLQVSCPYDS MKHWGRRKAW CRQLGEKGPC QRVVSTHNLW LLSFLRRWNG STAITDDTLG GTLTITLRNL QPHDAGLYQC QSLHGSEADT LRKVLVEVLA DPLDHRDAGD LWFPGESESF EDAHVEHSIS RSLLEGEIPF PPTSILLLLA CIFLIKILAA SALWAAAWHG QKPGTHPPSE LDCGHDPGYQ LQTLPGLRDT //