Polymeric immunoglobulin receptor

1XED, 2OCW, 3CHN, 3CM9, 5D4K528418703ENSG00000162896ENSMUSG00000026417P01833O70570NM_002644NM_011082NP_002635NP_035212Polymeric immunoglobulin receptor (pIgR) is a transmembrane protein that in humans is encoded by the PIGR gene. It is an Fc receptor which facilitates the transcytosis of the soluble polymeric isoforms of immunoglobulin A , and immune complexes. pIgRs are mainly located on the epithelial lining of mucosal surfaces of the gastrointestinal tract. The composition of the receptor is complex, including 6 immunoglobulin-like domains, a transmembrane region, and an intracellular domain. pIgR expression is under the strong regulation of cytokines, hormones, and pathogenic stimuli.1xed: Crystal Structure of a Ligand-Binding Domain of the Human Polymeric Ig Receptor, pIgR Polymeric immunoglobulin receptor (pIgR) is a transmembrane protein that in humans is encoded by the PIGR gene. It is an Fc receptor which facilitates the transcytosis of the soluble polymeric isoforms of immunoglobulin A , and immune complexes. pIgRs are mainly located on the epithelial lining of mucosal surfaces of the gastrointestinal tract. The composition of the receptor is complex, including 6 immunoglobulin-like domains, a transmembrane region, and an intracellular domain. pIgR expression is under the strong regulation of cytokines, hormones, and pathogenic stimuli. pIgR is produced among others by intestinal epithelial cells (IECs) and bronchial epithelial cells. pIgR belongs to the family of type I transmembrane proteins. The extracellular portion of the protein contains 6 domains: 5 evolutionary conserved immunoglobulin-like domains, and 1 non-homologous domain, which is involved in proteolytic cleavage of pIg-pIgR complex from the apical side of the IECs. The quite long intracellular domain of the receptor, alongside with the transmembrane region, is responsible for the transduction of highly conserved signals. During transcytosis, an essential part of pIgR, the secretory component, is attached to the ligand and later cleaved with the ligand to form fully functioning secreted IgA. Polymeric immunoglobulin receptor is responsible for transcytosis of soluble dimeric IgAs and immune complexes from the basolateral to the apical mucosal epithelial cell surface. pIgR has a strong specificity to polymeric immunoglobulins and is not responsive to monomeric immunoglobulin. The ligand’s J-chain is responsible for the binding of pIgR to its ligand. The process of transporting polymeric immunoglobulins from the basolateral to apical side, known as transcytosis, is composed of several distinct steps. Transcytosis is initiated by either the binding of dimeric IgA to the receptor or the phosphorylation of Ser-664 residue of the receptor. The internalization of both free and IgA-bound pIgR is mediated by clathrin coating. The internalized receptor is transported to basolateral early endosomes. The following step of transporting the pIgR across the cell (through tubulo-vesicular compartments to apical recycling endosome) is dependent on microtubules. When pIgR reaches the apical membrane, proteolytic cleavage generates either a free secretory component of SC-IgA complex , which is released to the apical lumen. Cleavage occurs at the junction of the transmembrane region of the receptor and domain 5. pIgRs are capable of capturing IgA bound to an antigen (Immune complexes (ICs)) with identical affinity as IgA and transport them to apical side. ICs result from the capture of an antigen by an antibody. IgA ICs are formed within the mucous membranes in response to foreign invasion. The accumulation of ICs on the basolateral side of mucous layers can have detrimental effects. Transcytosis of IgA ICs from the formation sites represents an important mechanism of eliminating circulating antigens and minimizing their negative effects. The expression of pIgR is critically regulated by the pro-inflammatory cytokines, such as IL-1, IL-4, TNF-α, and IFN-γ. The transcriptional regulation by different cytokines proceeds though similar pathways, involving the NF-kB feedback loop. Interaction of IL-1 and TNF-α with their receptors ultimately lead to transcriptional activation of PIGR gene due to nuclear translocation of NF-kB. NF-kB interacts with intron 1 of the PIGR gene to start pIgR mRNA synthesis. Besides NF-kB pathway, the transcriptional induction also proceeds in response to IFN-γ, upregulating the expression of pIgR. Additionally, instead of the usual antagonistic behavior, IL-4 acts synergistically with IFN-γ to induce pIgR transcription. Their combination exhibits an upregulating effect in PIGR expression because of the presence of STAT6 enhancer, the main downstream effector of IL-4, binding site in PIGR's intron 1. The level of pIgRs in the mucosal reproductive tract is highly dependent on the activity of sex hormones and correlates with estrous cycle phases. The peaks of pIgR expression at proestrus and estrus phases are due to the dominant activity of estrogen, which acts as a pIgR agonist. The low levels of pIgR during the diestrus are linked to the downregulating activity of progesterone, which peaks during this phase and is able to reverse the activity of estrogen. Androgens are the agonists of pIgR expression in both male and female reproductive tissues.