TREM2

Triggering receptor expressed on myeloid cells 2 also known as TREM-2 is a protein that in humans is encoded by the TREM2 gene.[5][6][7]

TREM2
Identifiers
Aliases	TREM2, TREM-2, Trem2a, Trem2b, Trem2c, triggering receptor expressed on myeloid cells 2, PLOSL2
External IDs	OMIM: 605086 MGI: 1913150 HomoloGene: 10352 GeneCards: TREM2
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p21.1 Start 41,158,506 bp[1] End 41,163,186 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 C Start 48,346,401 bp[2] End 48,354,147 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • scaffold protein binding • lipopolysaccharide binding • lipoteichoic acid binding • peptidoglycan binding • phospholipid binding • signaling receptor activity • amyloid-beta binding • high-density lipoprotein particle binding • lipid binding • low-density lipoprotein particle binding • apolipoprotein binding • apolipoprotein A-I binding • very-low-density lipoprotein particle binding • GO:0032403 macromolecular complex binding • lipoprotein particle binding • protein tyrosine kinase binding • GO:0001948 protein binding Cellular component • integral component of membrane • membrane • extracellular region • cell membrane • integral component of plasma membrane • intrinsic component of plasma membrane Biological process • dendritic cell differentiation • positive regulation of CD40 signaling pathway • positive regulation of calcium-mediated signaling • positive regulation of C-C chemokine receptor CCR7 signaling pathway • phagocytosis, engulfment • detection of peptidoglycan • humoral immune response • cellular response to lipoteichoic acid • positive regulation of protein localization to plasma membrane • regulation of immune response • positive regulation of peptidyl-tyrosine phosphorylation • detection of lipoteichoic acid • innate immune system • detection of lipopolysaccharide • cellular response to peptidoglycan • positive regulation of antigen processing and presentation of peptide antigen via MHC class II • positive regulation of ERK1 and ERK2 cascade • signal transduction • osteoclast differentiation • positive regulation of macrophage fusion • positive regulation of amyloid-beta clearance • positive regulation of protein phosphorylation • regulation of gene expression • negative regulation of autophagy • positive regulation of gene expression • positive regulation of mitochondrion organization • regulation of TOR signaling • positive regulation of TOR signaling • regulation of interleukin-6 production • regulation of peptidyl-tyrosine phosphorylation • positive regulation of chemotaxis • regulation of resting membrane potential • positive regulation of astrocyte activation • regulation of macrophage inflammatory protein 1 alpha production • import into cell • regulation of plasma membrane bounded cell projection organization • positive regulation of proteasomal protein catabolic process • positive regulation of inward rectifier potassium channel activity • regulation of intracellular signal transduction • positive regulation of microglial cell activation • negative regulation of autophagic cell death • positive regulation of microglial cell migration • cellular response to amyloid-beta • positive regulation of CAMKK-AMPK signaling cascade • positive regulation of ATP biosynthetic process • apoptotic cell clearance • positive regulation of protein secretion • microglial cell activation • response to ischemia • negative regulation of interleukin-1 beta production • negative regulation of tumor necrosis factor production • positive regulation of interleukin-10 production • negative regulation of apoptotic process • positive regulation of osteoclast differentiation • positive regulation of NIK/NF-kappaB signaling • microglial cell activation involved in immune response • defense response to bacterium • regulation of innate immune response • positive regulation of phagocytosis, engulfment • microglial cell proliferation • amyloid-beta clearance • complement-mediated synapse pruning • neuroinflammatory response • positive regulation of neuroinflammatory response • positive regulation of engulfment of apoptotic cell Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	54209	83433
Ensembl	ENSG00000095970	ENSMUSG00000023992
UniProt	Q9NZC2	Q99NH8
RefSeq (mRNA)	NM_001271821 NM_018965	NM_001272078 NM_031254
RefSeq (protein)	NP_001258750 NP_061838	NP_001259007 NP_112544
Location (UCSC)	Chr 6: 41.16 – 41.16 Mb	Chr 17: 48.35 – 48.35 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Monocyte/macrophage- and neutrophil-mediated inflammatory responses can be stimulated through a variety of receptors, including G protein-linked 7-transmembrane receptors (e.g., FPR1), Fc receptors, CD14 and Toll-like receptors (e.g., TLR4), and cytokine receptors (e.g., IFNGR1). Engagement of these receptors can also prime myeloid cells to respond to other stimuli. Myeloid cells express receptors belonging to the Immunoglobulin (Ig) superfamily, such as TREM2, or to the C-type lectin superfamily. Depending on their transmembrane and cytoplasmic sequence structure, these receptors have either activating (e.g., KIR2DS1) or inhibitory functions (e.g., KIR2DL1).[7]

Upon stimulation, TREM2 engages DAP12, causing the two tyrosines on its immunoreceptor tyrosine-based activation motif (ITAM) to become phosphorylated. Spleen tyrosine kinase (Syk) then docks to these phosphorylation sites and activates the phosphatidylinositol-3 kinase (PI3K) cascade which promotes several cellular functions such as cell survival, phagocytosis, pro-inflammatory cytokine production, and cytoskeletal rearrangement via various transcription factors including AP1, NF-κB, and NFAT.[8]

Clinical significance

Homozygous mutations in TREM2 are known to cause rare, autosomal recessive forms of dementia with an early onset and presenting with[6] or without[9] bone cysts and fractures.

A rare missense mutation (rs75932628-T) in the gene encoding TREM2, (predicted to result in an R47H substitution), confers a significant risk of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, it is suspected of interfering with the brain’s ability to prevent the buildup of plaque.[10][11] TREM2 mutations increase the risk of neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. TREM2 interacts with DAP12 in microglia to trigger phagocytosis of amyloid beta peptide and apoptotic neurons without inflammation. Mutations in TREM2 impair the normal proteolytic maturation of the protein which in turn interferes with phagocytosis and may therefore contribute to the pathogenesis of Alzheimer's disease.[12]

Soluble TREM2 has been detected in human cerebrospinal fluid (CSF), where it was found to be elevated in CSF of patients with multiple sclerosis and other inflammatory neurological conditions in comparison to patients without inflammatory neurologic disorders.[13]

A recent study from Cruchaga lab[14] identified MS4A4A as a major regulator of soluble TREM2 levels.[15] Cruchaga and his team also demonstrated that TREM2 is implicated on disease in general and not only in those individuals that carry TREM2 risk variants. Using Mendelian randomization, they also demonstrate that highly soluble TREM2 levels are protective. These results provide a mechanistic explanation of one the AD risk GWAS loci, MS4A4A: this gene modified risk for AD by modulating TREM2 levels.

TREM2 transcript levels are upregulated in the lung parenchyma of smokers.[16]

References

1. GRCh38: Ensembl release 89: ENSG00000095970 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000023992 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Bouchon A, Dietrich J, Colonna M (May 2000). "Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes". Journal of Immunology. 164 (10): 4991–5. doi:10.4049/jimmunol.164.10.4991. PMID 10799849.
6. Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L (September 2002). "Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype". American Journal of Human Genetics. 71 (3): 656–62. doi:10.1086/342259. PMC 379202. PMID 12080485.
7. "Entrez Gene: TREM2 triggering receptor expressed on myeloid cells 2".
8. Xing J, Titus AR, Humphrey MB (2015). "The TREM2-DAP12 signaling pathway in Nasu-Hakola disease: a molecular genetics perspective". Research and Reports in Biochemistry. 5: 89–100. doi:10.2147/RRBC.S58057. PMC 4605443. PMID 26478868.
9. Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, Dursun B, Bilgic B, Hanagasi H, Gurvit H, Emre M, Singleton A, Hardy J (January 2013). "Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement". JAMA Neurology. 70 (1): 78–84. doi:10.1001/jamaneurol.2013.579. PMC 4001789. PMID 23318515.
10. Hickman SE, El Khoury J (April 2014). "TREM2 and the neuroimmunology of Alzheimer's disease". Biochemical Pharmacology. 88 (4): 495–8. doi:10.1016/j.bcp.2013.11.021. PMC 3972304. PMID 24355566.
11. Kolata G (14 November 2012). "Alzheimer's Tied to Mutation Harming Immune Response". New York Times. Retrieved 15 November 2012.
12. Lue LF, Schmitz C, Walker DG (August 2015). "What happens to microglial TREM2 in Alzheimer's disease: Immunoregulatory turned into immunopathogenic?". Neuroscience. 302: 138–50. doi:10.1016/j.neuroscience.2014.09.050. PMID 25281879. S2CID 207254770.
13. Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, Rinker J, Naismith RT, Panina-Bordignon P, Passini N, Galimberti D, Scarpini E, Colonna M, Cross AH (November 2008). "Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation". Brain. 131 (Pt 11): 3081–91. doi:10.1093/brain/awn217. PMC 2577803. PMID 18790823.
14. "NeuroGenomics and Informatics".
15. Deming, Y; Filipello, F; Cignarella, F; Cantoni, C; Hsu, S; Mikesell, R; Li, Z; Del-Aguila, JL; Dube, U; Farias, FG; Bradley, J; Budde, J; Ibanez, L; Fernandez, MV; Blennow, K; Zetterberg, H; Heslegrave, A; Johansson, PM; Svensson, J; Nellgård, B; Lleo, A; Alcolea, D; Clarimon, J; Rami, L; Molinuevo, JL; Suárez-Calvet, M; Morenas-Rodríguez, E; Kleinberger, G; Ewers, M; Harari, O; Haass, C; Brett, TJ; Benitez, BA; Karch, CM; Piccio, L; Cruchaga, C (14 August 2019). "The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk". Science Translational Medicine. 11 (505): eaau2291. doi:10.1126/scitranslmed.aau2291. PMC 6697053. PMID 31413141.
16. Pintarelli G, Noci S, Maspero D, Pettinicchio A, Dugo M, De Cecco L, Incarbone M, Tosi D, Santambrogio L, Dragani TA, Colombo F (September 2019). "Cigarette smoke alters the transcriptome of non-involved lung tissue in lung adenocarcinoma patients". Scientific Reports. 9 (1): 13039. Bibcode:2019NatSR...913039P. doi:10.1038/s41598-019-49648-2. PMC 6736939. PMID 31506599.

Further reading

• Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, Rinker J, Naismith RT, Panina-Bordignon P, Passini N, Galimberti D, Scarpini E, Colonna M, Cross AH (November 2008). "Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation". Brain. 131 (Pt 11): 3081–91. doi:10.1093/brain/awn217. PMC 2577803. PMID 18790823.
• Allcock RJ, Barrow AD, Forbes S, Beck S, Trowsdale J (February 2003). "The human TREM gene cluster at 6p21.1 encodes both activating and inhibitory single IgV domain receptors and includes NKp44". European Journal of Immunology. 33 (2): 567–77. doi:10.1002/immu.200310033. PMID 12645956. S2CID 27147251.
• Soragna D, Papi L, Ratti MT, Sestini R, Tupler R, Montalbetti L (June 2003). "An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene". Journal of Neurology, Neurosurgery, and Psychiatry. 74 (6): 825–6. doi:10.1136/jnnp.74.6.825-a. PMC 1738498. PMID 12754369.
• Cella M, Buonsanti C, Strader C, Kondo T, Salmaggi A, Colonna M (August 2003). "Impaired differentiation of osteoclasts in TREM-2-deficient individuals". The Journal of Experimental Medicine. 198 (4): 645–51. doi:10.1084/jem.20022220. PMC 2194167. PMID 12913093.
• Paloneva J, Mandelin J, Kiialainen A, Bohling T, Prudlo J, Hakola P, Haltia M, Konttinen YT, Peltonen L (August 2003). "DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features". The Journal of Experimental Medicine. 198 (4): 669–75. doi:10.1084/jem.20030027. PMC 2194176. PMID 12925681.
• Montalbetti L, Ratti MT, Greco B, Aprile C, Moglia A, Soragna D (2005). "Neuropsychological tests and functional nuclear neuroimaging provide evidence of subclinical impairment in Nasu-Hakola disease heterozygotes". Functional Neurology. 20 (2): 71–5. PMID 15966270.
• Bianchin MM, Lima JE, Natel J, Sakamoto AC (February 2006). "The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2". Neurology. 66 (4): 615–6, author reply 615–6. doi:10.1212/01.wnl.0000216105.11788.0f. PMID 16505336.

External links

• GeneReviews/NIH/NCBI/UW entry on Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL)