Butyrophilin (BTN) family interactions (Homo sapiens)

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2, 5, 9, 12, 13101574, 61, 118314cytosolcytosolcytosolBTN1A1BTN3A1 BTNL9Resting T Cell surface BTNL8Activated T Cell surface BTNL9 BTN1A1:XDHBTN3A1 phosphoantigens(pAgs)BTN1A1 Activated T Cell surface CD209BTN3A1 BTN3A1,BTN1A1:PPLPPLBTNL8: resting Tcell surfaceBTN3A3 CD209 BTN1A1 BTN3A1,BTN1A1BTN2A2:activated TCell surfaceBTN3A1(BTN3A2,BTN3A3)BTN3A2 BTNL2: activated TCell surfaceBTN3A1 BTNL9:Immune cellsurfaceBTNL8 BTN3A1(BTN3A2,BTN3A3):pAgsBTN3A3 BTN2A2XDH Resting T CellsurfaceImmune Cell surfacePPL Immune Cell surface BTN3A2 XDHActivated T CellsurfaceBTN2A1phosphoantigens (pAgs) BTN2A2 BTNL2BTN2A1:CD209BTN2A1 BTN1A1 BTNL2


Description

Butyrophilins (BTNs) and butyrophilin like (BTNL) molecules are regulators of immune responses that belong to the immunoglobulin (Ig) superfamily of transmembrane proteins. They are structurally related to the B7 family of co-stimulatory molecules and have similar immunomodulatory functions (Afrache et al. 2012, Arnett & Viney 2014). BTNs are implicated in T cell development, activation and inhibition, as well as in the modulation of the interactions of T cells with antigen presenting cells and epithelial cells. Certain BTNsare genetically associated with autoimmune and inflammatory diseases (Abeler Domer et al. 2014).
The human butyrophilin family includes seven members that are subdivided into three subfamilies: BTN1, BTN2 and BTN3. The BTN1 subfamily contains only the prototypic single copy BTN1A1 gene, whereas the BTN2 and BTN3 subfamilies each contain three genes BTN2A1, BTN2A2 and BTN2A3, and BTN3A1, BTN3A2 and BTN3A3, respectively (note that BTN2A3 is a pseudogene). BTN1A1 has a crucial function in the secretion of lipids into milk (Ogg et al. 2004) and collectively, BTN2 and BTN3 proteins are cell surface transmembrane glycoproteins, that act as regulators of immune responses. BTNL proteins share considerable homology to the BTN family members. The human genome contains four BTNL genes: BTNL2, 3, 8 and 9 (Abeler Domer et al. 2014). View original pathway at Reactome.

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Pathway is converted from Reactome ID: 8851680
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Reactome version: 75
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Reactome Author: Garapati, Phani Vijay

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Bibliography

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  1. Sandstrom A, Peigné CM, Léger A, Crooks JE, Konczak F, Gesnel MC, Breathnach R, Bonneville M, Scotet E, Adams EJ.; ''The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells.''; PubMed Europe PMC Scholia
  2. Rhodes DA, Reith W, Trowsdale J.; ''Regulation of Immunity by Butyrophilins.''; PubMed Europe PMC Scholia
  3. Yamazaki T, Goya I, Graf D, Craig S, Martin-Orozco N, Dong C.; ''A butyrophilin family member critically inhibits T cell activation.''; PubMed Europe PMC Scholia
  4. Vorbach C, Scriven A, Capecchi MR.; ''The housekeeping gene xanthine oxidoreductase is necessary for milk fat droplet enveloping and secretion: gene sharing in the lactating mammary gland.''; PubMed Europe PMC Scholia
  5. Afrache H, Gouret P, Ainouche S, Pontarotti P, Olive D.; ''The butyrophilin (BTN) gene family: from milk fat to the regulation of the immune response.''; PubMed Europe PMC Scholia
  6. Jeong J, Rao AU, Xu J, Ogg SL, Hathout Y, Fenselau C, Mather IH.; ''The PRY/SPRY/B30.2 domain of butyrophilin 1A1 (BTN1A1) binds to xanthine oxidoreductase: implications for the function of BTN1A1 in the mammary gland and other tissues.''; PubMed Europe PMC Scholia
  7. Nguyen T, Liu XK, Zhang Y, Dong C.; ''BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation.''; PubMed Europe PMC Scholia
  8. Rhodes DA, Chen HC, Price AJ, Keeble AH, Davey MS, James LC, Eberl M, Trowsdale J.; ''Activation of human γδ T cells by cytosolic interactions of BTN3A1 with soluble phosphoantigens and the cytoskeletal adaptor periplakin.''; PubMed Europe PMC Scholia
  9. Abeler-Dörner L, Swamy M, Williams G, Hayday AC, Bas A.; ''Butyrophilins: an emerging family of immune regulators.''; PubMed Europe PMC Scholia
  10. Malcherek G, Mayr L, Roda-Navarro P, Rhodes D, Miller N, Trowsdale J.; ''The B7 homolog butyrophilin BTN2A1 is a novel ligand for DC-SIGN.''; PubMed Europe PMC Scholia
  11. Gu S, Nawrocka W, Adams EJ.; ''Sensing of Pyrophosphate Metabolites by Vγ9Vδ2 T Cells.''; PubMed Europe PMC Scholia
  12. Arnett HA, Viney JL.; ''Immune modulation by butyrophilins.''; PubMed Europe PMC Scholia
  13. Ogg SL, Weldon AK, Dobbie L, Smith AJ, Mather IH.; ''Expression of butyrophilin (Btn1a1) in lactating mammary gland is essential for the regulated secretion of milk-lipid droplets.''; PubMed Europe PMC Scholia
  14. Chapoval AI, Smithson G, Brunick L, Mesri M, Boldog FL, Andrew D, Khramtsov NV, Feshchenko EA, Starling GC, Mezes PS.; ''BTNL8, a butyrophilin-like molecule that costimulates the primary immune response.''; PubMed Europe PMC Scholia
  15. Smith IA, Knezevic BR, Ammann JU, Rhodes DA, Aw D, Palmer DB, Mather IH, Trowsdale J.; ''BTN1A1, the mammary gland butyrophilin, and BTN2A2 are both inhibitors of T cell activation.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114919view16:43, 25 January 2021ReactomeTeamReactome version 75
113364view11:43, 2 November 2020ReactomeTeamReactome version 74
112573view15:54, 9 October 2020ReactomeTeamReactome version 73
101487view11:34, 1 November 2018ReactomeTeamreactome version 66
101024view21:14, 31 October 2018ReactomeTeamreactome version 65
100559view19:48, 31 October 2018ReactomeTeamreactome version 64
100107view16:33, 31 October 2018ReactomeTeamreactome version 63
99657view15:04, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99258view12:45, 31 October 2018ReactomeTeamreactome version 62
93503view11:25, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
Activated T Cell surfaceR-ALL-8851965 (Reactome) This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.
Activated T Cell surface R-ALL-8851965 (Reactome) This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.
BTN1A1 ProteinQ13410 (Uniprot-TrEMBL)
BTN1A1:XDHComplexR-HSA-8851053 (Reactome)
BTN1A1ProteinQ13410 (Uniprot-TrEMBL)
BTN2A1 ProteinQ7KYR7 (Uniprot-TrEMBL)
BTN2A1:CD209ComplexR-HSA-8851051 (Reactome)
BTN2A1ProteinQ7KYR7 (Uniprot-TrEMBL)
BTN2A2 ProteinQ8WVV5 (Uniprot-TrEMBL)
BTN2A2:activated T Cell surfaceComplexR-HSA-8851970 (Reactome)
BTN2A2ProteinQ8WVV5 (Uniprot-TrEMBL)
BTN3A1 ProteinO00481 (Uniprot-TrEMBL)
BTN3A1(BTN3A2,BTN3A3):pAgsComplexR-HSA-8851039 (Reactome)
BTN3A1(BTN3A2,BTN3A3)ComplexR-HSA-8851035 (Reactome)
BTN3A1,BTN1A1:PPLComplexR-HSA-8938411 (Reactome)
BTN3A1,BTN1A1ComplexR-HSA-8938432 (Reactome)
BTN3A2 ProteinP78410 (Uniprot-TrEMBL)
BTN3A3 ProteinO00478 (Uniprot-TrEMBL)
BTNL2 ProteinQ9UIR0 (Uniprot-TrEMBL)
BTNL2: activated T Cell surfaceComplexR-HSA-8851977 (Reactome)
BTNL2ProteinQ9UIR0 (Uniprot-TrEMBL)
BTNL8 ProteinQ6UX41 (Uniprot-TrEMBL)
BTNL8: resting T cell surfaceComplexR-HSA-8851983 (Reactome)
BTNL8ProteinQ6UX41 (Uniprot-TrEMBL)
BTNL9 ProteinQ6UXG8 (Uniprot-TrEMBL)
BTNL9:Immune cell surfaceComplexR-HSA-8851986 (Reactome)
BTNL9ProteinQ6UXG8 (Uniprot-TrEMBL)
CD209 ProteinQ9NNX6 (Uniprot-TrEMBL)
CD209ProteinQ9NNX6 (Uniprot-TrEMBL)
Immune Cell surface R-ALL-8851998 (Reactome) This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.
Immune Cell surfaceR-ALL-8851998 (Reactome) This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.
PPL ProteinO60437 (Uniprot-TrEMBL)
PPLProteinO60437 (Uniprot-TrEMBL)
Resting T Cell surfaceR-ALL-8851976 (Reactome) This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.
Resting T Cell surface R-ALL-8851976 (Reactome) This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.
XDH ProteinP47989 (Uniprot-TrEMBL)
XDHProteinP47989 (Uniprot-TrEMBL)
phosphoantigens (pAgs)R-ALL-8851032 (Reactome)
phosphoantigens (pAgs) R-ALL-8851032 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
Activated T Cell surfaceR-HSA-8851988 (Reactome)
Activated T Cell surfaceR-HSA-8852010 (Reactome)
BTN1A1:XDHArrowR-HSA-8851044 (Reactome)
BTN1A1R-HSA-8851044 (Reactome)
BTN2A1:CD209ArrowR-HSA-8851018 (Reactome)
BTN2A1R-HSA-8851018 (Reactome)
BTN2A2:activated T Cell surfaceArrowR-HSA-8851988 (Reactome)
BTN2A2R-HSA-8851988 (Reactome)
BTN3A1(BTN3A2,BTN3A3):pAgsArrowR-HSA-8851038 (Reactome)
BTN3A1(BTN3A2,BTN3A3)R-HSA-8851038 (Reactome)
BTN3A1,BTN1A1:PPLArrowR-HSA-8938431 (Reactome)
BTN3A1,BTN1A1R-HSA-8938431 (Reactome)
BTNL2: activated T Cell surfaceArrowR-HSA-8852010 (Reactome)
BTNL2R-HSA-8852010 (Reactome)
BTNL8: resting T cell surfaceArrowR-HSA-8852013 (Reactome)
BTNL8R-HSA-8852013 (Reactome)
BTNL9:Immune cell surfaceArrowR-HSA-8851979 (Reactome)
BTNL9R-HSA-8851979 (Reactome)
CD209R-HSA-8851018 (Reactome)
Immune Cell surfaceR-HSA-8851979 (Reactome)
PPLR-HSA-8938431 (Reactome)
R-HSA-8851018 (Reactome) Butyrophilin 2A1 (BTN2A1) can bind to a lectin molecule, DC-specific ICAM3-grabbing non-integrin (DC-SIGN; also known as CD209), found on monocytes and dendritic cells. Binding of DC-SIGN is dependent on the tumor- and/or tissue-specific high-mannose glycosylation of BTN2A1 (Malcherek et al. 2007). BTN2A1 may represent a susceptibility gene for metabolic syndrome and myocardial infarction through an effect on dyslipidaemia (Fujimaki et al. 2011, Hiramatsu et al. 2012, Yamada et al. 2011, Arnett & Viney 2014).
R-HSA-8851038 (Reactome) Butyrophilin 3A1 (BTN3A1) directly binds to small pyrophosphate containing organic molecules known as prenyl pyrophosphates or phosphoantigens (pAgs). These molecules are produced either endogenously, such as isopentenyl pyrophosphate (IPP), an intermediate of the mevalonate pathway in human cells that can accumulate intracellularly during tumorigenesis, or by microbes, such as hydroxy-methyl-butyl-pyrophosphate (HDMAPP, also known as HMBPP), a microbial intermediate of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway. This interaction causes a conformational change in the extracellular domain of BTN3A1, which then leads to the activation of a specialized subset of gamma/delta T cells Vgamma9Vdelta2. The other two members of the BTN3A family, BTN3A2 and BTN3A3 may also be involved in the activation process (Sandstrom et al. 2014).
R-HSA-8851044 (Reactome) The B30.2 cytoplasmic domain (PRY/SPRY domain) of Butyrophilin 1A1 (BTN1A1) binds the enzyme xanthine oxidoreductase (XDH). This interaction provides scaffolding function, stabilizes the milk fat globule membrane (MFGM), and aids in milk fat globule secretion (Jeong et al. 2009).
R-HSA-8851979 (Reactome) Butyrophilin-like protein 9 (BTNL9) is expressed in a variety of tissues in humans and mice. No known function has been ascribed to BTNL9 but recombinant BTNL9-Fc has been shown to bind to many immune cells including T cells, B cells, macrophages and dendritic cells (Yamazaki et al. 2010).
R-HSA-8851988 (Reactome) BTN2A2 protein is upregulated upon T cell activation and interacts with activated T cells suggesting the presence of one or more receptors on these cells. It has been demonstrated that BTN2A2 inhibits T cell metabolism upon binding to its putative receptor on T cells (Smith et al. 2010).
R-HSA-8852010 (Reactome) Butyrophilin-like 2 (BTNL2), is a butyrophilin family member with homology to the B7 costimulatory molecules. BTNL2 binds to a putative receptor on activated T cells and functions to have an inhibitory effect on CD4+ T cell proliferation (Nguyen et al. 2006). It may also bind to receptors on liver and vascular endothelium in mouse (Arnett et al. 2007). Polymorphisms in BTNL2 have been linked with various autoimmune and inflammatory diseases (Pathan et al. 2009, Mochida et al. 2009, Arnett & Viney 2014).
R-HSA-8852013 (Reactome) Human BTNL8 (butyrophilin like 8), shares characteristics of both B7 and BTN like (BTNL) proteins. BTNL8 was shown to interact with a putative receptor on the surface of resting T cells but not activated T cells, and is able to promote activation of resting T lymphocytes (Chapoval et al. 2013).
R-HSA-8938431 (Reactome) Periplakin (PPL) is a 195-kDa cytosolic protein of the cytoskeleton-associated plakin family. BTN3A1 and BTN1A1 are shown to interact with PPL with a membrane-proximal di-leucine motif located in their cytoplasmic tail (Rhodes et al. 2015).
Resting T Cell surfaceR-HSA-8852013 (Reactome)
XDHR-HSA-8851044 (Reactome)
phosphoantigens (pAgs)R-HSA-8851038 (Reactome)
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