Polymeric immunoglobulin receptor (pIgR) is a
transmembrane protein
A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...
that in humans is encoded by the ''PIGR''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
It is an
Fc receptor
In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platele ...
which facilitates the
transcytosis
Transcytosis (also known as cytopempsis) is a type of transcellular transport in which various macromolecules are transported across the interior of a cell (biology), cell. Macromolecules are captured in Vesicle (biology), vesicles on one side of ...
of the soluble polymeric isoforms of
immunoglobulin A
Immunoglobulin A (IgA, also referred to as sIgA in its secretory form) is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other ty ...
and
immunoglobulin M
Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen;
causing it to also ...
(pIg) and
immune complex
An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen of ...
es. 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.
Structure
pIgR is produced among others by
intestinal epithelial cells (IECs) and bronchial epithelial cells. pIgR belongs to the family of type I
transmembrane protein
A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...
s. 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
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...
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.
During
transcytosis
Transcytosis (also known as cytopempsis) is a type of transcellular transport in which various macromolecules are transported across the interior of a cell (biology), cell. Macromolecules are captured in Vesicle (biology), vesicles on one side of ...
, 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.
History
Per Brandtzaeg showed that secretory component acts as a plasma membrane receptor on epithelial cells for polymeric immunoglobulin A and immunoglobulin M.
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.
Keith Mostov
Keith E. Mostov is an American cell biologist. He received a BA from University of Chicago in 1976 and during 1976–77 he was a Rhodes Scholar at New College, Oxford. Mostov received a PhD in Biological Science from the Rockefeller University in ...
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
Function
Polymeric immunoglobulin receptor is responsible for transcytosis of soluble
dimeric IgA, pentameric IgM, and
immune complex
An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen of ...
es 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.
Transcytosis

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
Clathrin is a protein that plays a role in the formation of coated vesicles. Clathrin was first isolated by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskel ...
coating. The internalized receptor is transported to basolateral early
endosome
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of the endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membra ...
s. The following step of transporting the pIgR across the cell (through tubulo-vesicular compartments to apical recycling endosome) is dependent on
microtubule
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nanometer, nm and have an inner diameter bet ...
s.
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.
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.
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.
Regulation
Cytokinetic Regulation
The expression of pIgR is critically regulated by the pro-inflammatory cytokines, such as
IL-1,
IL-4,
TNF-α
Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
, and
IFN-γ
Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...
. 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.
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.
Hormonal Regulation
The level of pIgRs in the mucosal reproductive tract is highly dependent on the activity of
sex hormones
Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects a ...
and correlates with
estrous cycle
The estrous cycle (, originally ) is a set of recurring physiological changes induced by reproductive hormones in females of mammalian subclass Theria. Estrous cycles start after sexual maturity in females and are interrupted by anestrous phase ...
phases. The peaks of pIgR expression at proestrus and estrus phases are due to the dominant activity of
estrogen
Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
, which acts as a pIgR agonist. The low levels of pIgR during the diestrus are linked to the downregulating activity of
progesterone
Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
, which peaks during this phase and is able to reverse the activity of estrogen.
Androgen
An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
s are the agonists of pIgR expression in both male and female reproductive tissues.
5’-flanking region of the ''Pigr'' gene contains a response element to
glucocorticoid
Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
s. This class of hormones increases the steady mRNA expression levels of pIgR of intestinal cells.
Prolactin
Prolactin (PRL), also known as lactotropin and mammotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secr ...
elevates the levels of IRF-1 via
Jak-STAT pathway
The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumor formation. The pathway communicates information from chemical signals outs ...
. 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.
Pathogenic Stimulation
IECs express a variety of
Toll-like receptor
Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane protein, single-spanning receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophages ...
s (TLRs), activation of which ultimately leads to the pIgR upregulation during the infection.
The most prominent modulators of pIgR regulation consist of
TLR4
Toll-like receptor 4 (TLR4), also designated as CD284 (cluster of differentiation 284), is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approx ...
and
TLR3
Toll-like receptor 3 (TLR3) also known as CD283 (cluster of differentiation 283) is a protein that in humans is encoded by the ''TLR3'' gene. TLR3 is a member of the toll-like receptor family of pattern recognition receptors of the innate immune ...
, which recognize bacterial
lipopolysaccharide
Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...
and viral dsRNA respectively. TLR4, like the majority of TLRs, transduce the signal though
MyD88
Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the ''MYD88'' gene. originally discovered in the laboratory of Dan A. Liebermann (Lord et al. Oncogene 1990) as a Myeloid differentiation primary resp ...
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.
References
Further reading
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External links
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{{NLM content
Fc receptors