FCAR
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Fc fragment of IgA receptor (FCAR) is a human gene[3] that codes for the transmembrane receptor FcαRI, also known as CD89 (Cluster of Differentiation 89). FcαRI binds the heavy-chain constant region of Immunoglobulin A (IgA) antibodies.[4] FcαRI is present on the cell surface of myeloid lineage cells, including neutrophils, monocytes, macrophages, and eosinophils,[5] though it is notably absent from intestinal macrophages[6] and does not appear on mast cells.[5] FcαRI plays a role in both pro- and anti-inflammatory responses depending on the state of IgA bound.[5] Inside-out signaling primes FcαRI in order for it to bind its ligand,[4] while outside-in signaling caused by ligand binding depends on FcαRI association with the Fc receptor gamma chain (FcR γ-chain).[5]
Though FcαRI is part of the Fc receptor immunoglobulin superfamily, the protein's primary structure is similar to receptors in the leukocyte receptor cluster (LRC), and the FCAR gene appears amidst LRC genes on chromosome 19.[4][5] This contrasts with the location of other members of the Fc receptor immunoglobulin superfamily, which are encoded on chromosome 1.[4][5] Additionally, though there are equivalents to FCAR in several species, there is no such homolog in mice.[4]
Structure
The FcαRI α-chain consists of two extracellular domains, EC1 and EC2, at a right angle to each other, a transmembrane domain, and an intracellular domain.[4] However, this chain alone cannot perform signaling in response to IgA binding, and FcαRI must associate with a dimeric form of FcR g-chain, the ends of which contain immunoreceptor tyrosine-based activation motifs (ITAMs). The FcR γ-chain is responsible for relaying the signal to the inside of the cell.[4][5]
Two FCAR alleles differing by a
Inside-Out Signaling
FcαRI must first be primed by a process called inside-out signaling in order to bind with increased ability to IgA. Priming occurs when cytokines signaling the presence of an infection bind their receptors on FcαRI-expressing cells, activating the kinase PI3K. PI3K then activates p38 and PKC, which together with PP2A lead to the dephosphorylation of the Serine 263 residue (Ser263) on the intracellular domain of the FcαRI α-chain.[8] The priming of FcαRI to be able to bind IgA does not depend on FcαRI association with the FcR γ-chain,[5] but does depend on cytoskeleton organization.[8]
Once primed, FcαRI can bind IgA.[8] The FcαRI EC1 domain binds the hinge between the IgA-Fc regions Ca2 and Ca3 regions.[4]
Function
Signaling and the resulting cellular response caused by FcαRI binding IgA varies depending on the state of the IgA molecules. A pro-inflammatory response is signaled when IgA molecules in an
Despite signaling via ITAMs, which typically initiate activation cascades, FcαRI may either act as an activating or inhibitory receptor.[10] Inhibitory ITAM signaling (ITAMi) results in anti-inflammatory responses. When FcαRI monovalently binds monomeric, non-antigen bound IgA, the form most common in serum,[4] the resulting signals result in inactivation of other activating receptors such as FcγR and FcεRI. The binding of the monomeric serum IgA causes Lyn to only partly phosphorylate the FcR γ-chain ITAMs. Consequently, Src homology region 2 domain-containing phosphatase-1 (SHP-1) is recruited by Syk to the FcR γ-chain.[9] A tyrosine phosphatase, SHP-1 coordinates the anti-inflammatory response, preventing other receptors from signaling for pro-inflammatory responses by not allowing these receptors to become phosphorylated.[9] This ITAMi signaling supports homeostasis in the absence of pathogens.[9]
The anti-inflammatory role of monomeric IgA-FcαRI binding may have implications for treatment of allergic asthma, as shown by targeting FcαRI in transgenic mice models with anti-FcαRI Fab antibodies, which mimic the binding of monomeric IgA.[11] This FcαRI targeting led to decreased infiltration of airway tissue by inflammatory leukocytes.[11]
The secreted form of IgA (sIgA), a homodimer secreted across epithelial linings such as the gut epithelium, is sterically hindered in its binding to FcαRI. This is because some of sIgA's FcαRI binding site is obscured by a section of the cleaved polymeric Ig receptor that aided sIgA's secretion into the gut lumen.[5] However, the precursor to sIgA, dimeric IgA (dIgA), binds to FcαRI with approximately the same affinity as monomeric IgA.[5] Secreted IgA plays an important role in preventing immune response to commensal gut microbes, and accordingly intestinal macrophages do not express FcαRI.[4] However, during invasion of mucosal tissue by pathogenic bacteria, neutrophils responding to the infection will bind and phagocytose dIgA-opsonized bacteria via FcαRI.[4]
FcαRI is also an important Fc receptor for neutrophil killing of tumor cells. When FcαRI-expressing neutrophils come into contact with IgA-opsonized tumor cells, the neutrophils not only perform antibody-dependent cell-mediated cytotoxicity, but also release the cytokines TNF-α and IL-1β which cause increased neutrophil migration to the site.[12]
Interactions
FCAR has been shown to
See also
References
- ^ a b c ENSG00000284004, ENSG00000273738, ENSG00000283953, ENSG00000276985, ENSG00000275970, ENSG00000284061, ENSG00000283750, ENSG00000278415, ENSG00000186431, ENSG00000275136, ENSG00000276858, ENSG00000284245, ENSG00000275269, ENSG00000274580 GRCh38: Ensembl release 89: ENSG00000275564, ENSG00000284004, ENSG00000273738, ENSG00000283953, ENSG00000276985, ENSG00000275970, ENSG00000284061, ENSG00000283750, ENSG00000278415, ENSG00000186431, ENSG00000275136, ENSG00000276858, ENSG00000284245, ENSG00000275269, ENSG00000274580 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: FCAR Fc fragment of IgA, receptor for".
- ^ PMID 21937986.
- ^ S2CID 21300390.
- PMID 11509607.
- ^ PMID 17339498.
- ^ S2CID 20610179.
- ^ PMID 23201915.
- PMID 26497513.
- ^ PMID 15664157.
- PMID 23287459.
- PMID 8530370.
Further reading
- Morton HC, van Egmond M, van de Winkel JG (1996). "Structure and function of human IgA Fc receptors (Fc alpha R)". PMID 8954257.
- Morton HC, Brandtzaeg P (2001). "CD89: the human myeloid IgA Fc receptor". Archivum Immunologiae et Therapiae Experimentalis. 49 (3): 217–29. PMID 11478396.
- Martin AM, Kulski JK, Witt C, Pontarotti P, Christiansen FT (February 2002). "Leukocyte Ig-like receptor complex (LRC) in mice and men". Trends in Immunology. 23 (2): 81–8. PMID 11929131.
- Monteiro RC, Van De Winkel JG (2003). "IgA Fc receptors". Annual Review of Immunology. 21: 177–204. PMID 12524384.
- Kremer EJ, Kalatzis V, Baker E, Callen DF, S2CID 22356303.
- Maliszewski CR, March CJ, Schoenborn MA, Gimpel S, Shen L (December 1990). "Expression cloning of a human Fc receptor for IgA". The Journal of Experimental Medicine. 172 (6): 1665–72. PMID 2258698.
- Pfefferkorn LC, Yeaman GR (October 1994). "Association of IgA-Fc receptors (Fc alpha R) with Fc epsilon RI gamma 2 subunits in U937 cells. Aggregation induces the tyrosine phosphorylation of gamma 2". Journal of Immunology. 153 (7): 3228–36. S2CID 44693625.
- de Wit TP, Morton HC, Capel PJ, van de Winkel JG (August 1995). "Structure of the gene for the human myeloid IgA Fc receptor (CD89)". Journal of Immunology. 155 (3): 1203–9. S2CID 12283570.
- Dürrbaum-Landmann I, Kaltenhäuser E, Flad HD, Ernst M (April 1994). "HIV-1 envelope protein gp120 affects phenotype and function of monocytes in vitro". Journal of Leukocyte Biology. 55 (4): 545–51. S2CID 44412688.
- Monteiro RC, Hostoffer RW, Cooper MD, Bonner JR, Gartland GL, Kubagawa H (October 1993). "Definition of immunoglobulin A receptors on eosinophils and their enhanced expression in allergic individuals". The Journal of Clinical Investigation. 92 (4): 1681–5. PMID 8408621.
- Morton HC, Schiel AE, Janssen SW, van de Winkel JG (1996). "Alternatively spliced forms of the human myeloid Fc alpha receptor (CD89) in neutrophils". Immunogenetics. 43 (4): 246–7. PMID 8575829.
- Patry C, Sibille Y, Lehuen A, Monteiro RC (June 1996). "Identification of Fc alpha receptor (CD89) isoforms generated by alternative splicing that are differentially expressed between blood monocytes and alveolar macrophages". Journal of Immunology. 156 (11): 4442–8. S2CID 45370016.
- Carayannopoulos L, Hexham JM, Capra JD (April 1996). "Localization of the binding site for the monocyte immunoglobulin (Ig) A-Fc receptor (CD89) to the domain boundary between Calpha2 and Calpha3 in human IgA1". The Journal of Experimental Medicine. 183 (4): 1579–86. PMID 8666916.
- Pleass RJ, Andrews PD, Kerr MA, Woof JM (September 1996). "Alternative splicing of the human IgA Fc receptor CD89 in neutrophils and eosinophils". The Biochemical Journal. 318 ( Pt 3) (3): 771–7. PMID 8836118.
- Reterink TJ, Verweij CL, van Es LA, Daha MR (October 1996). "Alternative splicing of IgA Fc receptor (CD89) transcripts". Gene. 175 (1–2): 279–80. PMID 8917112.
- van Dijk TB, Bracke M, Caldenhoven E, Raaijmakers JA, Lammers JW, Koenderman L, de Groot RP (December 1996). "Cloning and characterization of Fc alpha Rb, a novel Fc alpha receptor (CD89) isoform expressed in eosinophils and neutrophils". Blood. 88 (11): 4229–38. PMID 8943858.
- Toyabe S, Kuwano Y, Takeda K, Uchiyama M, Abo T (November 1997). "IgA nephropathy-specific expression of the IgA Fc receptors (CD89) on blood phagocytic cells". Clinical and Experimental Immunology. 110 (2): 226–32. PMID 9367406.
- Gulle H, Samstag A, Eibl MM, Wolf HM (January 1998). "Physical and functional association of Fc alpha R with protein tyrosine kinase Lyn". Blood. 91 (2): 383–91. PMID 9427690.
External links
- CD89+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.