PIGR
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPIGR, Pigr, polymeric immunoglobulin receptor
External IDsOMIM: 173880 MGI: 103080 HomoloGene: 1984 GeneCards: PIGR
Orthologs
SpeciesHumanMouse
Entrez

5284

18703

Ensembl

ENSG00000162896

ENSMUSG00000026417

UniProt

P01833

O70570

RefSeq (mRNA)

NM_002644

NM_011082

RefSeq (protein)

NP_002635

NP_035212

Location (UCSC)Chr 1: 206.93 – 206.95 MbChr 1: 130.75 – 130.78 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Polymeric immunoglobulin receptor (pIgR) is a transmembrane protein that in humans is encoded by the PIGR gene.[5] It is an Fc receptor which facilitates the transcytosis of the soluble polymeric isoforms of immunoglobulin A and immunoglobulin M (pIg) 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.[6] pIgR expression is under the strong regulation of cytokines, hormones, and pathogenic stimuli.[6][7]

Structure

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,[8] 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, along with the transmembrane region, is responsible for the transduction of highly conserved signals.[7][9] 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.[10]

History

Per Brandtzaeg showed that secretory component acts as a plasma membrane receptor on epithelial cells for polymeric immunoglobulin A and immunoglobulin M.[11] This was paradoxical, as secretory component is a soluble protein, whereas plasma membrane receptors are transmembrane proteins. Numerous models were proposed for how secretory component might work as a receptor, though none of these models resolved this paradox.[11] Keith Mostov and colleagues found that secretory component was a proteolytic fragment of a transmembrane precursor, the pIgR, which led them to propose the currently accepted model[12]

Function

Polymeric immunoglobulin receptor is responsible for transcytosis of soluble dimeric IgA, pentameric IgM, 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.[13] The ligand’s J-chain is responsible for the binding of pIgR to its ligand.[7][10]

Transcytosis

The diagram represents the process of transcytosis of dimeric IgA / free polymeric immunoglobulin receptor from the basolateral to apical side of a mucosal epithelial cell.

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.[9] 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.[9] 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.[7] Cleavage occurs at the junction of the transmembrane region of the receptor and domain 5.[6]

Elimination of Immune Complexes

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.[14] 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.[14][15]

Regulation

Cytokinetic Regulation

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 through 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.[6]

Besides NF-kB pathway, the transcriptional induction also proceeds in response to IFN-γ, upregulating the expression of pIgR.[6][7]

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.[16]

Hormonal Regulation

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.[17] Androgens are the agonists of pIgR expression in both male and female reproductive tissues.[6]

5’-flanking region of the Pigr gene contains a response element to glucocorticoids. This class of hormones increases the steady mRNA expression levels of pIgR of intestinal cells.[16][18]

Prolactin elevates the levels of IRF-1 via Jak-STAT pathway. IRF-1 is known to be a direct agonist of pIgR expression. Considering this linkage, prolactin is believed to exhibit indirect upregulation of pIgR levels during pregnancy and lactation.[6]

Pathogenic Stimulation

IECs express a variety of Toll-like receptors (TLRs), activation of which ultimately leads to the pIgR upregulation during the infection.[6][7] The most prominent modulators of pIgR regulation consist of TLR4 and TLR3, which recognize bacterial lipopolysaccharide and viral dsRNA respectively. TLR4, like the majority of TLRs, transduce the signal though MyD88 adaptor and execute the function via NF-kB, which stimulates the expression of pIgR by binding to intron 1 of the gene. TLR3, on the other hand, involves the regulation by the means of IRF-1, which is able to promote the transcription of PIGR gene by binding to exon 1.[16][18]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162896 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000026417 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: PIGR polymeric immunoglobulin receptor".
  6. 1 2 3 4 5 6 7 8 Kaetzel CS (August 2005). "The polymeric immunoglobulin receptor: bridging innate and adaptive immune responses at mucosal surfaces". Immunological Reviews. 206: 83–99. doi:10.1111/j.0105-2896.2005.00278.x. PMID 16048543. S2CID 43588042.
  7. 1 2 3 4 5 6 Asano M, Komiyama K (June 2011). "Polymeric immunoglobulin receptor". Journal of Oral Science. 53 (2): 147–156. doi:10.2334/josnusd.53.147. PMID 21712618.
  8. ↑ Williams, Alan F. (March 1984). "Immunology: The immunoglobulin superfamily takes shape". Nature. 308 (5954): 12–13. Bibcode:1984Natur.308...12W. doi:10.1038/308012a0. ISSN 1476-4687. PMID 6700707. S2CID 4356420.
  9. 1 2 3 Mostov K (December 1991). "The polymeric immunoglobulin receptor". Seminars in Cell Biology. 2 (6): 411–418. PMID 1813030.
  10. 1 2 Owen, Judith A; Punt, Jenni; Stranford, Sharon A; Jones, Patricia P; Kuby, Janis (2013). Kuby immunology. New York: W.H. Freeman. ISBN 9781429219198. OCLC 820117219.
  11. 1 2 Brandtzaeg P (May 1981). "Transport models for secretory IgA and secretory IgM". Clinical and Experimental Immunology. 44 (2): 221–232. PMC 1537350. PMID 6118214.
  12. ↑ Mostov KE, Kraehenbuhl JP, Blobel G (December 1980). "Receptor-mediated transcellular transport of immunoglobulin: synthesis of secretory component as multiple and larger transmembrane forms". Proceedings of the National Academy of Sciences of the United States of America. 77 (12): 7257–7261. Bibcode:1980PNAS...77.7257M. doi:10.1073/pnas.77.12.7257. PMC 350481. PMID 6938972.
  13. ↑ Kaetzel CS, Blanch VJ, Hempen PM, Phillips KM, Piskurich JF, Youngman KR (May 1997). "The polymeric immunoglobulin receptor: structure and synthesis". Biochemical Society Transactions. 25 (2): 475–480. doi:10.1042/bst0250475. PMID 9191139.
  14. 1 2 Kaetzel CS, Robinson JK, Chintalacharuvu KR, Vaerman JP, Lamm ME (October 1991). "The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: a local defense function for IgA". Proceedings of the National Academy of Sciences of the United States of America. 88 (19): 8796–8800. Bibcode:1991PNAS...88.8796K. doi:10.1073/pnas.88.19.8796. PMC 52597. PMID 1924341.
  15. ↑ Phalipon A, Corthésy B (February 2003). "Novel functions of the polymeric Ig receptor: well beyond transport of immunoglobulins". Trends in Immunology. 24 (2): 55–58. doi:10.1016/s1471-4906(02)00031-5. PMID 12547499.
  16. 1 2 3 Johansen FE, Kaetzel CS (November 2011). "Regulation of the polymeric immunoglobulin receptor and IgA transport: new advances in environmental factors that stimulate pIgR expression and its role in mucosal immunity". Mucosal Immunology. 4 (6): 598–602. doi:10.1038/mi.2011.37. PMC 3196803. PMID 21956244.
  17. ↑ Kaushic C, Richardson JM, Wira CR (July 1995). "Regulation of polymeric immunoglobulin A receptor messenger ribonucleic acid expression in rodent uteri: effect of sex hormones". Endocrinology. 136 (7): 2836–2844. doi:10.1210/endo.136.7.7789308. PMID 7789308.
  18. 1 2 Kaetzel CS (December 2014). "Cooperativity among secretory IgA, the polymeric immunoglobulin receptor, and the gut microbiota promotes host-microbial mutualism". Immunology Letters. 162 (2 Pt A): 10–21. doi:10.1016/j.imlet.2014.05.008. PMC 4246051. PMID 24877874.

Further reading

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