FCAR

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{{#invoke:Infobox_gene|getTemplateData}} Fc fragment of IgA receptor (FCAR) is a human gene<ref name="entrez22">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> that codes for the transmembrane receptor FcαRI, also known as CD89 (Cluster of Differentiation 89). FcαRI binds the heavy-chain constant region of Immunoglubulin A (IgA) antibodies.<ref name="Bakema_2011">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> FcαRI is present on the cell surface of myeloid lineage cells, including neutrophils, monocytes, macrophages, and eosinophils,<ref name="Aleyd_2015">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> though it is notably absent from intestinal macrophages<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> and does not appear on mast cells.<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[edit]

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 (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 (SNP) code for two FcαRI molecules that differ in their ability to signal for IL-6 and TNF-α production and release.<ref name="Wu_2007">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</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 isoforms.<ref name="entrez22"/>

Inside-Out Signaling[edit]

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.<ref name="Brandsma_2015">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</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[edit]

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 ITAMs by Lyn.<ref name="Mkaddem_2013">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref> Syk, a tyrosine kinase, subsequently docks at the phosphorylated ITAMs and initiates PI3K and PLC-γ signaling.<ref name="Mkaddem_2013" /> The ensuing signaling cascades lead to pro-inflammatory responses such as release of cytokines, phagocytosis, respiratory bursts, 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>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</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 (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">{{#invoke:Citation/CS1|citation |CitationClass=journal }}</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 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 IL-1β which cause increased neutrophil migration to the site.<ref>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

Interactions[edit]

FCAR has been shown to interact with FCGR1A.<ref name=pmid8530370>{{#invoke:Citation/CS1|citation |CitationClass=journal }}</ref>

See also[edit]

References[edit]

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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