FCAR

2018-06-25T20:40:33Z

50.225.173.234: Minor edits for grammar.

{{Infobox_gene}}
'''Fc fragment of IgA receptor''' ('''''FCAR''''') is a human [[gene]]<ref name="entrez22">{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2204|title=Entrez Gene: FCAR Fc fragment of IgA, receptor for|accessdate=}}</ref> that codes for the transmembrane receptor '''FcαRI''', also known as '''CD89''' ('''C'''luster of '''D'''ifferentiation '''89'''). FcαRI binds the heavy-chain constant region of Immunoglubulin A ([[Immunoglobulin A|IgA]]) antibodies.<ref name="Bakema_2011">{{cite journal | vauthors = Bakema JE, van Egmond M | title = The human immunoglobulin A Fc receptor FcαRI: a multifaceted regulator of mucosal immunity | journal = Mucosal Immunology | volume = 4 | issue = 6 | pages = 612–24 | date = November 2011 | pmid = 21937986 | doi = 10.1038/mi.2011.36 }}</ref> FcαRI is present on the cell surface of myeloid lineage cells, including [[neutrophil]]s, [[monocyte]]s, [[macrophage]]s, and [[eosinophil]]s,<ref name="Aleyd_2015">{{cite journal | vauthors = Aleyd E, Heineke MH, van Egmond M | title = The era of the immunoglobulin A Fc receptor FcαRI; its function and potential as target in disease | journal = Immunological Reviews | volume = 268 | issue = 1 | pages = 123–38 | date = November 2015 | pmid = 26497517 | doi = 10.1111/imr.12337 }}</ref> though it is notably absent from intestinal macrophages<ref>{{cite journal | vauthors = Smith PD, Smythies LE, Mosteller-Barnum M, Sibley DA, Russell MW, Merger M, Sellers MT, Orenstein JM, Shimada T, Graham MF, Kubagawa H | title = Intestinal macrophages lack CD14 and CD89 and consequently are down-regulated for LPS- and IgA-mediated activities | journal = Journal of Immunology | volume = 167 | issue = 5 | pages = 2651–6 | date = September 2001 | pmid = 11509607 | doi = 10.4049/jimmunol.167.5.2651 }}</ref> and does not appear on [[mast cell]]s.<ref name="Aleyd_2015" /> FcαRI plays a role in both pro- and anti-inflammatory responses depending on the state of IgA bound.<ref name="Aleyd_2015" /> Inside-out signaling primes FcαRI in order for it to bind its ligand,<ref name="Bakema_2011" /> while outside-in signaling caused by ligand binding depends on FcαRI association with the Fc receptor gamma chain (FcR γ-chain).<ref name="Aleyd_2015" />

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.<ref name="Bakema_2011" /><ref name="Aleyd_2015" /> This contrasts with the location of other members of the Fc receptor immunoglobulin superfamily, which are encoded on chromosome 1.<ref name="Bakema_2011" /><ref name="Aleyd_2015" /> Additionally, though there are equivalents to ''FCAR'' in several species, there is no such homolog in mice.<ref name="Bakema_2011" />

== 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.<ref name="Bakema_2011" /> 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 ([[Immunoreceptor tyrosine-based activation motif|ITAMs]]). The FcR γ-chain is responsible for relaying the signal to the inside of the cell.<ref name="Bakema_2011" /><ref name="Aleyd_2015" />

Two ''FCAR'' alleles differing by a [[Single-nucleotide polymorphism|single nucleotide polymorphism]] (SNP) code for two FcαRI molecules that differ in their ability to signal for [[Interleukin 6|IL-6]] and [[Tumor necrosis factor alpha|TNF-α]] production and release.<ref name="Wu_2007">{{cite journal | vauthors = Wu J, Ji C, Xie F, Langefeld CD, Qian K, Gibson AW, Edberg JC, Kimberly RP | title = FcalphaRI (CD89) alleles determine the proinflammatory potential of serum IgA | journal = Journal of Immunology | volume = 178 | issue = 6 | pages = 3973–82 | date = March 2007 | pmid = 17339498 | doi = 10.4049/jimmunol.178.6.3973 }}</ref> The SNP results in either serine or glycine as the 248th residue of the amino acid sequence, a position in the intracellular domain of FcαRI.<ref name="Wu_2007" /> Compared to FcαRI with Ser248, FcαRI molecules with Gly248 are better able to signal for the release of IL-6, even independently from FcR γ-chain association.<ref name="Wu_2007" />

[[Alternative splicing]] of the transcript from this gene produces ten mRNA variants encoding different [[Protein isoforms|isoforms]].<ref name="entrez22"/>

== 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 [[Phosphoinositide 3-kinase|PI3K]]. PI3K then activates [[P38 mitogen-activated protein kinases|p38]] and [[Protein kinase C|PKC]], which together with [[Protein phosphatase 2|PP2A]] lead to the dephosphorylation of the Serine 263 residue (Ser263) on the intracellular domain of the FcαRI α-chain.<ref name="Brandsma_2015">{{cite journal | vauthors = Brandsma AM, Jacobino SR, Meyer S, ten Broeke T, Leusen JH | title = Fc receptor inside-out signaling and possible impact on antibody therapy | journal = Immunological Reviews | volume = 268 | issue = 1 | pages = 74–87 | date = November 2015 | pmid = 26497514 | doi = 10.1111/imr.12332 }}</ref> The priming of FcαRI to be able to bind IgA does not depend on FcαRI association with the FcR γ-chain,<ref name="Aleyd_2015" /> but does depend on cytoskeleton organization.<ref name="Brandsma_2015" />

Once primed, FcαRI can bind IgA.<ref name="Brandsma_2015" /> The FcαRI EC1 domain binds the hinge between the IgA-Fc regions Ca2 and Ca3 regions.<ref name="Bakema_2011" />

== 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 [[immune complex]] bind to multiple FcαRI, resulting in the activation of ''Src'' family kinases and the phosphorylation of the FcR γ-chain [[Immunoreceptor tyrosine-based activation motif|ITAMs]] by [[LYN|Lyn]].<ref name="Mkaddem_2013">{{cite journal | vauthors = Mkaddem SB, Rossato E, Heming N, Monteiro RC | title = Anti-inflammatory role of the IgA Fc receptor (CD89): from autoimmunity to therapeutic perspectives | journal = Autoimmunity Reviews | volume = 12 | issue = 6 | pages = 666–9 | date = April 2013 | pmid = 23201915 | doi = 10.1016/j.autrev.2012.10.011 }}</ref> [[Syk]], a tyrosine kinase, subsequently docks at the phosphorylated ITAMs and initiates [[Phosphoinositide 3-kinase|PI3K]] and [[Phosphoinositide phospholipase C|PLC-γ]] signaling.<ref name="Mkaddem_2013" /> The ensuing signaling cascades lead to pro-inflammatory responses such as release of [[cytokine]]s, [[phagocytosis]], [[respiratory burst]]s, [[antibody-dependent cell-mediated cytotoxicity]], production of [[reactive oxygen species]], and antigen presentation.<ref name="Bakema_2011" /><ref name="Aleyd_2015" />

Despite signaling via ITAMs, which typically initiate activation cascades, FcαRI may either act as an activating or inhibitory receptor.<ref>{{cite journal | vauthors = Getahun A, Cambier JC | title = Of ITIMs, ITAMs, and ITAMis: revisiting immunoglobulin Fc receptor signaling | journal = Immunological Reviews | volume = 268 | issue = 1 | pages = 66–73 | date = November 2015 | pmid = 26497513 | pmc = 4621791 | doi = 10.1111/imr.12336 }}</ref> Inhibitory ITAM signaling (ITAMi) results in anti-inflammatory responses. When FcαRI monovalently binds monomeric, non-antigen bound IgA, the form most common in serum,<ref name="Bakema_2011" /> 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 ([[PTPN6|SHP-1]]) is recruited by Syk to the FcR γ-chain.<ref name="Mkaddem_2013" /> 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.<ref name="Mkaddem_2013" /> This ITAMi signaling supports homeostasis in the absence of pathogens.<ref name="Mkaddem_2013" />

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.<ref name="Pasquier_2005">{{cite journal | vauthors = Pasquier B, Launay P, Kanamaru Y, Moura IC, Pfirsch S, Ruffié C, Hénin D, Benhamou M, Pretolani M, Blank U, Monteiro RC | title = Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM | journal = Immunity | volume = 22 | issue = 1 | pages = 31–42 | date = January 2005 | pmid = 15664157 | doi = 10.1016/j.immuni.2004.11.017 }}</ref> This FcαRI targeting led to decreased infiltration of airway tissue by inflammatory leukocytes.<ref name="Pasquier_2005" />

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 immunoglobulin receptor|polymeric Ig receptor]] that aided sIgA’s secretion into the gut lumen.<ref name="Aleyd_2015" /> However, the precursor to sIgA, dimeric IgA (dIgA), binds to FcαRI with approximately the same affinity as monomeric IgA.<ref name="Aleyd_2015" /> Secreted IgA plays an important role in preventing immune response to commensal gut microbes, and accordingly intestinal macrophages do not express FcαRI.<ref name="Bakema_2011" /> However, during invasion of mucosal tissue by pathogenic bacteria, neutrophils responding to the infection will bind and phagocytose dIgA-opsonized bacteria via FcαRI.<ref name="Bakema_2011" />

FcαRI is also an important Fc receptor for neutrophil killing of tumor cells. When FcαRI-expressing neutrophils come into contact with IgA-opsinized tumor cells, the neutrophils not only perform antibody-dependent cell-mediated cytotoxicity, but also release the cytokines TNF-α and [[Interleukin 1 beta|IL-1β]] which cause increased neutrophil migration to the site.<ref>{{cite journal | vauthors = van Egmond M, Bakema JE | title = Neutrophils as effector cells for antibody-based immunotherapy of cancer | journal = Seminars in Cancer Biology | volume = 23 | issue = 3 | pages = 190–9 | date = June 2013 | pmid = 23287459 | doi = 10.1016/j.semcancer.2012.12.002 }}</ref>

== Interactions ==

FCAR has been shown to [[Protein-protein interaction|interact]] with [[FCGR1A]].<ref name=pmid8530370>{{cite journal | vauthors = Morton HC, van den Herik-Oudijk IE, Vossebeld P, Snijders A, Verhoeven AJ, Capel PJ, van de Winkel JG | title = Functional association between the human myeloid immunoglobulin A Fc receptor (CD89) and FcR gamma chain. Molecular basis for CD89/FcR gamma chain association | journal = The Journal of Biological Chemistry | volume = 270 | issue = 50 | pages = 29781–7 | date = December 1995 | pmid = 8530370 | doi = 10.1074/jbc.270.50.29781 }}</ref>

== See also ==
* [[Cluster of differentiation]]

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Morton HC, van Egmond M, van de Winkel JG | title = Structure and function of human IgA Fc receptors (Fc alpha R) | journal = [[Critical Reviews in Immunology]] | volume = 16 | issue = 4 | pages = 423–40 | year = 1996 | pmid = 8954257 | doi = }}
* {{cite journal | vauthors = Morton HC, Brandtzaeg P | title = CD89: the human myeloid IgA Fc receptor | journal = Archivum Immunologiae Et Therapiae Experimentalis | volume = 49 | issue = 3 | pages = 217–29 | year = 2001 | pmid = 11478396 | doi = }}
* {{cite journal | vauthors = Martin AM, Kulski JK, Witt C, Pontarotti P, Christiansen FT | title = Leukocyte Ig-like receptor complex (LRC) in mice and men | journal = Trends in Immunology | volume = 23 | issue = 2 | pages = 81–8 | date = February 2002 | pmid = 11929131 | doi = 10.1016/S1471-4906(01)02155-X }}
* {{cite journal | vauthors = Monteiro RC, Van De Winkel JG | title = IgA Fc receptors | journal = Annual Review of Immunology | volume = 21 | issue = | pages = 177–204 | year = 2003 | pmid = 12524384 | doi = 10.1146/annurev.immunol.21.120601.141011 }}
* {{cite journal | vauthors = Kremer EJ, Kalatzis V, Baker E, Callen DF, Sutherland GR, Maliszewski CR | title = The gene for the human IgA Fc receptor maps to 19q13.4 | journal = Human Genetics | volume = 89 | issue = 1 | pages = 107–8 | date = April 1992 | pmid = 1577457 | doi = 10.1007/BF00207054 }}
* {{cite journal | vauthors = Maliszewski CR, March CJ, Schoenborn MA, Gimpel S, Shen L | title = Expression cloning of a human Fc receptor for IgA | journal = The Journal of Experimental Medicine | volume = 172 | issue = 6 | pages = 1665–72 | date = December 1990 | pmid = 2258698 | pmc = 2188749 | doi = 10.1084/jem.172.6.1665 }}
* {{cite journal | vauthors = Pfefferkorn LC, Yeaman GR | title = 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 = Journal of Immunology | volume = 153 | issue = 7 | pages = 3228–36 | date = October 1994 | pmid = 7522255 | doi = }}
* {{cite journal | vauthors = de Wit TP, Morton HC, Capel PJ, van de Winkel JG | title = Structure of the gene for the human myeloid IgA Fc receptor (CD89) | journal = Journal of Immunology | volume = 155 | issue = 3 | pages = 1203–9 | date = August 1995 | pmid = 7636188 | doi = }}
* {{cite journal | vauthors = Dürrbaum-Landmann I, Kaltenhäuser E, Flad HD, Ernst M | title = HIV-1 envelope protein gp120 affects phenotype and function of monocytes in vitro | journal = Journal of Leukocyte Biology | volume = 55 | issue = 4 | pages = 545–51 | date = April 1994 | pmid = 8145026 | doi = }}
* {{cite journal | vauthors = Monteiro RC, Hostoffer RW, Cooper MD, Bonner JR, Gartland GL, Kubagawa H | title = Definition of immunoglobulin A receptors on eosinophils and their enhanced expression in allergic individuals | journal = The Journal of Clinical Investigation | volume = 92 | issue = 4 | pages = 1681–5 | date = October 1993 | pmid = 8408621 | pmc = 288327 | doi = 10.1172/JCI116754 }}
* {{cite journal | vauthors = Morton HC, Schiel AE, Janssen SW, van de Winkel JG | title = Alternatively spliced forms of the human myeloid Fc alpha receptor (CD89) in neutrophils | journal = Immunogenetics | volume = 43 | issue = 4 | pages = 246–7 | year = 1996 | pmid = 8575829 | doi = 10.1007/s002510050057 }}
* {{cite journal | vauthors = Patry C, Sibille Y, Lehuen A, Monteiro RC | title = Identification of Fc alpha receptor (CD89) isoforms generated by alternative splicing that are differentially expressed between blood monocytes and alveolar macrophages | journal = Journal of Immunology | volume = 156 | issue = 11 | pages = 4442–8 | date = June 1996 | pmid = 8666819 | doi = }}
* {{cite journal | vauthors = Carayannopoulos L, Hexham JM, Capra JD | title = 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 | journal = The Journal of Experimental Medicine | volume = 183 | issue = 4 | pages = 1579–86 | date = April 1996 | pmid = 8666916 | pmc = 2192530 | doi = 10.1084/jem.183.4.1579 }}
* {{cite journal | vauthors = Pleass RJ, Andrews PD, Kerr MA, Woof JM | title = Alternative splicing of the human IgA Fc receptor CD89 in neutrophils and eosinophils | journal = The Biochemical Journal | volume = 318 ( Pt 3) | issue = 3 | pages = 771–7 | date = September 1996 | pmid = 8836118 | pmc = 1217685 | doi = }}
* {{cite journal | vauthors = Reterink TJ, Verweij CL, van Es LA, Daha MR | title = Alternative splicing of IgA Fc receptor (CD89) transcripts | journal = Gene | volume = 175 | issue = 1-2 | pages = 279–80 | date = October 1996 | pmid = 8917112 | doi = 10.1016/0378-1119(96)00152-7 }}
* {{cite journal | vauthors = van Dijk TB, Bracke M, Caldenhoven E, Raaijmakers JA, Lammers JW, Koenderman L, de Groot RP | title = Cloning and characterization of Fc alpha Rb, a novel Fc alpha receptor (CD89) isoform expressed in eosinophils and neutrophils | journal = Blood | volume = 88 | issue = 11 | pages = 4229–38 | date = December 1996 | pmid = 8943858 | doi = }}
* {{cite journal | vauthors = Toyabe S, Kuwano Y, Takeda K, Uchiyama M, Abo T | title = IgA nephropathy-specific expression of the IgA Fc receptors (CD89) on blood phagocytic cells | journal = Clinical and Experimental Immunology | volume = 110 | issue = 2 | pages = 226–32 | date = November 1997 | pmid = 9367406 | pmc = 2265504 | doi = 10.1111/j.1365-2249.1997.tb08321.x }}
* {{cite journal | vauthors = Gulle H, Samstag A, Eibl MM, Wolf HM | title = Physical and functional association of Fc alpha R with protein tyrosine kinase Lyn | journal = Blood | volume = 91 | issue = 2 | pages = 383–91 | date = January 1998 | pmid = 9427690 | doi = }}
{{refend}}

== External links ==
* {{MeshName|CD89+protein,+human}}

{{NLM content}}
{{PDB Gallery|geneid=2204}}
{{Clusters of differentiation}}
{{Immune receptors}}

[[Category:Clusters of differentiation]]
[[Category:Fc receptors]]

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FCAR