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J chain
J chain
J chain
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JCHAIN
Identifiers
AliasesJCHAIN, IGCJ, JCH, IGJ, J chain, joining chain of multimeric IgA and IgM
External IDsOMIM: 147790; MGI: 96493; HomoloGene: 16958; GeneCards: JCHAIN; OMA:JCHAIN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3512

16069

Ensembl

ENSG00000132465

ENSMUSG00000067149

UniProt

P01591

P01592

RefSeq (mRNA)

NM_144646

NM_152839

RefSeq (protein)

NP_653247

NP_690052

Location (UCSC)Chr 4: 70.66 – 70.68 MbChr 5: 88.67 – 88.68 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Immunoglobulin M (IgM) pentameric antibody molecule (consisting of five base units).
1: Base unit.
2: Heavy chains.
3: Light chains.
4: J chain.
5: Intermolecular disulfide bonds.
Schematic of immunoglobulin A dimer showing H-chain (blue), L-chain (red), J-chain (magenta) and secretory component (yellow).

The Joining (J) chain is a protein component that links monomers of antibodies IgM and IgA to form polymeric antibodies capable of secretion.[5] The J chain is well conserved in the animal kingdom, but its specific functions are yet to be fully understood. It is a 137 residue polypeptide,[6] encoded by the IGJ gene.[7][8][9]

Structure

[edit]

The J chain is a glycoprotein of molecular weight 15 kDa. Its secondary structure remains undetermined but is believed to adopt either a single β-barrel or two-domain folded structure with standard immunoglobulin domains.[10] The J chain's primary structure is unusually acidic having a high content of negatively charged amino acids.[11] It has 8 cysteine residues, 6 of which are involved in intramolecular disulfide bonds while the remaining two function to bind the Fc tailpiece regions of IgA or IgM antibodies, the α chain and μ chain respectively. An N-linked carbohydrate resulting from N-glycosylation is also essential in the protein's incorporation to antibody polymers.[12] There is no known protein family with significant homology to the J chain.[13]

Function

[edit]

Antibody polymerization

[edit]

The J chain regulates the multimerization of IgM and IgA in mammals. When expressed in cells, it favors the formation of a pentameric IgM and an IgA dimer. IgM pentamers are most commonly found with a single J chain, but some studies have seen as many as 4 J chains associated to a single IgM pentamer.

The J chain is incorporated late in the formation of IgM polymers and thermodynamically favors the formation of pentamers as opposed to hexamers.[12] In J chain-knockout (KO) mice, the hexameric IgM polymer dominates.[14] These J chain negative IgM hexamers are 15-20 times more effective at activating complement than J chain positive IgM pentamers.[15] However, J chain-KO mice have been shown have low concentrations of hexameric IgM and a deficiency in complement activation, suggesting additional in vivo regulatory mechanisms.[16] Another consequence of pentameric IgM reduced complement activation is its allowance of J chain positive pIgM to bind antigen without causing excessive damage to epithelial membranes through complement activation.[17]

The J chain facilitates IgA dimerization by linking two monomer secretory tails. Structurally, the J chain joins two antibody monomers asymmetrically by forming intermolecular disulfide bonds and bringing hydrophobic β-sandwiches on each molecule together.[18] This multimerization mechanism involves chaperone proteins including binding immunoglobulin protein (BiP) and MZB1 each sequentially recruiting distinct factors of the polymerized antibody.[19]

Antibody secretion

[edit]

Mucosal membrane antibody secretion from the basal membrane to apical epithelial cells is facilitated by the polymeric Ig receptor (pIgR). A basal protein of the pIgR known as secretory component (SC) recognizes Ig ready for secretion.[20] The binding between the secretory component and secretory Ig is facilitated by the antibody's J chain which makes physical contact with the secretory component in order to change the transporter's conformation to an open state.[21] The complex is then transcytosed and the secretory component proteolytically cleaved from the receptor releasing the antibody to the apical side of the epithelial cell and to the lumen at large. This mechanism is thought to be largely conserved between the secretion of IgM and IgA.[19]

Regulation

[edit]

J chain was originally believed to only be expressed in antibody-secreting plasma cells, however, the J chain has been seen to be expressed in earlier stages of B cell differentiation prior to Ig expression.[22] J chain expression is believed to occur in the early stages of lymphoid cell differentiation as it is expressed in both B and T cell precursors. As cells develop, it seems that expression of the μ-chain becomes necessary for J chain synthesis.[23]

The J chain gene is transcriptionally regulated through canonical Pax5 repression.[24] As Pax5 is a common transcriptional regulator, the J chain is still expressed in plasma cells that secrete monomeric antibodies. In such cells it is believed to provide no function and is quickly degraded.[19] In plasma cells that secrete monomeric IgA, a Pax5-independent mechanism is likely to prevent IgA dimerization.[25]

Phylogeny

[edit]

The J chain is likely to have evolutionarily arisen in early jaw-boned vertebrates.[26] Groups of bony fish including teleosts have since lost J chain expression.[13]  Xenopus are able to polymerize mucosal IgX in the absence of J chain, perhaps due to a loss of the conserved cysteine residues that link the J chain and Ig secretory tail.[27]

Sharks do not express IgA and thus use J chain expression solely for the polymerization of IgM.[28] This makes sharks an intriguing model organism in studying J chain regulation and polymerization without the confounding variables of mucosal secretion.[29]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

J chain

View on Grokipedia
from Grokipedia
The J chain, also known as the joining chain or immunoglobulin J chain, is a small polypeptide glycoprotein that serves as an essential component in the assembly and secretion of polymeric forms of the antibodies immunoglobulin M (IgM) and immunoglobulin A (IgA). It consists of approximately 137 amino acids, with a molecular weight of 15-16 kDa, including six intrachain and two interchain cysteine residues that form disulfide bonds critical for linking immunoglobulin monomers, as well as a single N-linked glycan that constitutes about 8% of its mass and is vital for association with IgA. Encoded by the IGJ gene, the J chain is produced by certain B cells, particularly plasma cells in mucosal and glandular tissues, and is not found in a free form outside of cells but exclusively within polymeric immunoglobulin complexes. In its primary function, the J chain regulates the of immunoglobulins by linking two units—typically forming dimers for IgA or serving as a nucleating unit for pentameric IgM—thereby enabling these antibodies to achieve high valency for binding, which is particularly suited for agglutinating pathogens at mucosal surfaces without triggering strong responses like complement activation. The J chain also exhibits activity, attracting immune cells to sites of . For IgM, the J chain is required for the efficient of pentameric forms but not for their initial assembly, while for IgA, it is indispensable for dimerization and subsequent transport. This also creates specific binding sites on the J chain that interact with the polymeric immunoglobulin receptor (pIgR), also known as the secretory component (SC), facilitating the of these antibodies across epithelial cells into exocrine to form secretory IgA (sIgA) and secretory IgM (sIgM). The biological significance of the J chain lies in its pivotal role in mucosal immunity, where polymeric IgA and IgM act as the first line of defense against pathogens by neutralizing them at barrier sites such as the respiratory, gastrointestinal, and genitourinary tracts. Without the J chain, polymeric immunoglobulins fail to bind pIgR effectively, leading to impaired secretion and reduced immune protection at these interfaces. Structural studies from 2020 and 2024 have further elucidated how the J chain caps the assembly of immunoglobulin tailpieces and bridges interactions between the Fc regions of IgM and pIgR, ensuring stable multimer formation and receptor-mediated transport. Defects in J chain expression or function have been associated with altered polymerization and potential immune deficiencies, underscoring its importance in adaptive immunity.

Structure

Primary Sequence

The mature J chain is a polypeptide of 137 residues with a molecular weight of approximately 15 kDa. This linear sequence features 8 residues, 6 of which form three intramolecular bonds to stabilize the chain's backbone, while the other 2 enable intermolecular linkages with the penultimate residues in the heavy chains of polymeric immunoglobulins. The J chain exhibits a high negative charge, arising from 7 and 5 residues that collectively contribute to its acidic (pI ≈ 4.7) and exceptional solubility in aqueous environments.

Tertiary Structure

The J chain exhibits a compact, globular tertiary dominated by β-sheets, forming a β-sandwich-like domain that serves as a scaffold for immunoglobulin . This fold, resolved through cryo-electron (cryo-EM) structures of IgM and IgA complexes, consists of a central core with four antiparallel β-strands (β1 to β4) flanked by loops and three protruding β-hairpins, which extend outward as two distinct "wings" (W1 and W2) to engage the heavy-chain tailpieces of adjacent monomers. Three intramolecular disulfide bridges stabilize the core fold of the J chain, linking conserved residues to maintain the β-sandwich architecture and prevent unfolding under physiological conditions; these bridges are essential for the protein's structural integrity prior to assembly with immunoglobulins. The residues involved in these s contribute to the compact domain formation, as detailed in the primary . The C-terminal region of the J chain features an exposed β-hairpin loop that projects away from , positioning it for hydrophobic and electrostatic interactions with the Fc tailpieces of IgM or IgA heavy chains during dimer nucleation. This region remains accessible in the folded state, facilitating the initial linkages that initiate without occluding the binding interface. Although the J chain lacks to the , its β-sandwich fold bears structural resemblance to the compact, -stabilized domains of other small glycoproteins, such as those in viral proteins or certain cytokines, highlighting a toward stable, multimeric assembly roles. Cryo-EM data from and murine complexes confirm this architecture is highly conserved across , with no significant deviations in fold.

Post-Translational Modifications

The J chain, a small polypeptide essential for the of IgM and IgA, undergoes a single N-linked at residue 49 (Asn49), which represents its primary . This site is conserved across humans and other vertebrates, featuring complex N-glycans that include biantennary structures with varying sialylation levels, such as 30% disialylated forms and 15% with terminal residues. The absence of or other major modifications, such as or ubiquitination, has been consistently observed in proteomic analyses of the J chain. This N-linked at Asn49 plays a critical role in efficient assembly by stabilizing interactions between the J chain and the Fc regions of IgM and IgA heavy chains. experiments replacing Asn49 with (N49A) in IgA1 systems result in markedly reduced dimer formation, with the unglycosylated J chain exhibiting impaired incorporation due to altered conformational dynamics and inability to form stable bonds within the polymer. Similar impairments in J chain integration occur in IgM assembly, where unglycosylation reduces and may favor J chain-deficient polymeric forms. These findings underscore the glycan's necessity for positioning the J chain correctly during late-stage assembly in the . Beyond assembly, the Asn49 glycan enhances the overall stability of the J chain-Ig complex, shielding it from proteolytic degradation and promoting efficient of polymeric antibodies. assays show that removal of this glycan destabilizes the Fc-J chain interface, increasing susceptibility to intracellular degradation pathways, while glycosylated forms facilitate transit through the secretory pathway and reduce aggregation. This protective effect ensures that only properly assembled polymers are exported, minimizing the release of non-functional monomers.

Function

Antibody Polymerization

The J chain facilitates the of immunoglobulins IgM and IgA by forming bonds between its residues at positions 14 and 69 and the penultimate cysteine in the heavy chain tailpieces of the respective monomers. This covalent linkage assembles five IgM monomers into a pentamer and two IgA monomers into a dimer, stabilizing the multimeric structures essential for their effector functions. The process occurs intracellularly in plasma cells, where the J chain coordinates the oxidative assembly of these polymers through interactions with the constant domains of the heavy chains. The of polymerization requires exactly one J chain per unit, ensuring precise multimer formation; excess or absence disrupts this balance. Structural studies indicate that the Cμ3 and Cμ4 domains of IgM, along with the μ tailpiece, are critical for incorporating the J chain into pentamers, while for IgA, the Cα3 domain and α tailpiece drive dimerization. In J chain-deficient models, such as hybridoma cell lines and mice, IgM is impaired, leading to the production of aberrant hexameric forms lacking the J chain instead of the standard pentamer. These hexamers activate complement 15- to 20-fold more efficiently than J chain-containing pentamers, highlighting the J chain's role in preventing overly potent, non-standard polymers that could disrupt immune . In vitro assembly experiments and analyses of J chain mice further demonstrate that the J chain is indispensable for correct , as its absence results in heterogeneous oligomers with reduced efficiency and altered complement-fixing capacity.

Antibody Secretion

The J chain plays a pivotal role in the epithelial transport of polymeric by enabling their specific interaction with the polymeric immunoglobulin receptor (pIgR) on the basolateral membranes of epithelial cells. This interaction occurs through a high-affinity formed by the J chain within polymeric IgA (pIgA) dimers or IgM pentamers, allowing these immunoglobulins to be recognized and internalized by pIgR, which is also known as the transmembrane secretory component. The process begins with the non-covalent binding of J chain-containing polymeric to domain 1 of pIgR on the basolateral surface, followed by clathrin-mediated of the complex. The containing the pIg-pIgR complex is then transported vectorially through the epithelial cell to the apical membrane via vesicular trafficking. At the apical surface, endoproteolytic cleavage by a host releases the secretory component (SC)—the ectoplasmic portion of pIgR—bound to the polymeric , forming secretory IgA (SIgA) or secretory IgM (SIgM), which is secreted into the mucosal lumen to provide immune protection. This transport mechanism exhibits strict specificity for polymeric forms of IgA and IgM that contain the J chain, as monomeric immunoglobulins lack the requisite binding affinity for pIgR and are not efficiently transcytosed. In contrast, J chain incorporation ensures selective uptake and delivery of multivalent antibodies to mucosal surfaces, enhancing their role in local immunity without systemic circulation. Evidence from J chain knockout studies in mice demonstrates impaired mucosal IgA secretion, with elevated serum IgA levels (predominantly monomeric) and significantly reduced biliary and fecal IgA, indicating defective pIgR-mediated transport. These mice exhibit a lack of association between IgA and secretory component in mucosal secretions, further confirming that the J chain is essential for stable polymeric antibody delivery across epithelial barriers and effective mucosal defense.

Chemokine Activity

The joining (J) chain has emerged as an evolutionarily co-opted member of the family, indicating a potential role in immune cell recruitment beyond its traditional involvement in assembly. This co-option occurred through of an ancestral CXCL gene in the gnathostome common ancestor, positioning the JCHAIN locus adjacent to CXCL chemokine clusters on human chromosome 4q13.1 and conserved syntenic regions in other vertebrates, such as . Structurally, the J chain exhibits hallmark features of , including four with identical 1-2-2 phases, a conserved CXC motif encoded in exon 2, and similar exon lengths for the and mature protein domains. Crystal structures reveal a shared beta-strand core with CXCL8 (IL-8), though the J chain diverges with unique intrachain disulfide bonds and an extended C-terminal region that echoes motifs responsible for receptor binding and interactions. This C-terminal extension likely facilitates functional , with the core scaffold preserved independently of , as the defining motifs rely on primary sequence conservation rather than post-translational additions. A 2024 study in PNAS demonstrated this heritage through and structural analyses. Expressed in dendritic cells, muscle, and epithelial tissues, the J chain may retain primordial signaling roles that complement adaptive responses, highlighting its multifunctional evolution in immunity.

Regulation

The , encoding the immunoglobulin J chain, is located on the long arm of human at cytogenetic band 4q13.3. This positioning was determined through somatic cell hybrid analysis and techniques. The promoter region of JCHAIN is primarily regulated by the Pax5 (also known as BSAP), which functions in a B cell-specific manner to control activation during lymphocyte development. Pax5 binds to a negative regulatory motif within the promoter, repressing transcription in immature B cells to prevent untimely J chain production; this repression is alleviated by signals such as interleukin-2 during terminal differentiation. Reporter gene assays, including constructs driven by the JCHAIN promoter, have demonstrated Pax5-mediated repression. Electrophoretic mobility shift assays further confirmed specific binding of Pax5 to the promoter motif, showing high-affinity interaction that is disrupted by IL-2 signaling, leading to derepression. In Pax5-deficient models, JCHAIN mRNA levels are elevated, underscoring the repressive role of Pax5. J chain expression is tightly restricted to cell precursors, such as pre-B cells, and to mature plasma cells specialized in secreting polymeric IgM or IgA . In early precursors, J chain mRNA and protein synthesis initiate prior to full immunoglobulin assembly, serving as an early marker of B lineage commitment. In plasma cells, expression is markedly upregulated, with JCHAIN mRNA levels higher compared to resting B cells, correlating directly with polymeric antibody output.

Protein Stability

The J chain exhibits rapid degradation through the ubiquitin-proteasome pathway in cells that do not synthesize polymeric immunoglobulins, such as IgM or IgA, where it remains unassembled and is recognized as a misfolded substrate by the endoplasmic reticulum-associated degradation (ERAD) machinery. This process involves retrotranslocation of the J chain from the ER to the , followed by ubiquitination and proteasomal breakdown, ensuring that free J chain does not accumulate and potentially disrupt cellular . Recent biochemical studies have demonstrated that J chain oligomers, formed due to improper bonding, are specifically targeted for reduction and degradation by ER-resident enzymes like ERdj5 prior to proteasomal disposal. Stability of the J chain is markedly enhanced through its binding to immunoglobulin heavy chains during co-translational assembly in the ER, which incorporates it into polymeric structures and protects it from ERAD. In the absence of such assembly, the J chain undergoes rapid intracellular turnover, but association with heavy chains shifts its fate toward as part of the , preventing degradation. N-glycosylation plays a in maintaining J chain conformation by facilitating proper folding and inhibiting misfolding or aggregation, which would otherwise trigger ERAD. The single N-glycosylation site on the J chain contributes to overall structural integrity, as its removal leads to diminished stability and impaired dimerization in polymeric IgA assemblies. Pulse-chase experiments in myeloma cell lines have shown that co-expression of IgM significantly extends the intracellular of the J chain by promoting its incorporation into pentameric structures, contrasting with its short-lived presence in cells lacking IgM synthesis where degradation predominates. These findings underscore the J chain's dependence on polymeric Ig co-assembly for persistence beyond the ER.

Phylogeny

Evolutionary Origins

The J chain originated in jawed vertebrates, known as gnathostomes, approximately 500 million years ago, coinciding with the emergence of adaptive immunity. This timing aligns with the of immunoglobulin-based humoral responses, where the J chain became integral to the polymerization of early isotypes. The J chain co-evolved alongside the IgM and IgA genes, adapting to facilitate the assembly of multimeric antibodies through disulfide bond formation at the C-termini of their heavy chains. Recent genomic analyses indicate that the J chain arose as an evolutionarily co-opted protein from a chemokine-like ancestor within the CXCL family, repurposed from its original role in immune cell chemotaxis to support antibody structure. This co-option likely enhanced the efficiency of mucosal and systemic immunity in early vertebrates. Gene duplication events in the gnathostome played a key role in the J chain's emergence, with the duplicating from an adjacent CXCL gene while retaining shared -intron structures. However, the gene was subsequently lost in certain lineages, such as actinopterygians (ray-finned fishes), though it persists in chondrichthyans (cartilaginous fishes), highlighting lineage-specific evolutionary pressures. across jawed vertebrates reveals conserved residues, particularly the CXC motif in exon 2, which underpin the protein's bonding capabilities despite functional divergences from its progenitor.

Species Distribution

The J chain is universally present in mammals, where it facilitates the of IgM into pentamers and IgA into dimers or larger multimers for mucosal immunity. In birds, the J chain similarly supports IgM and IgA assembly, maintaining a conserved role in secretory antibody formation despite avian-specific isotypes like IgY. This presence extends to all examined mammalian orders and avian species, underscoring its essential function in higher vertebrates' humoral responses. In amphibians and reptiles, the J chain is retained and expressed in immune tissues, enabling IgM polymerization. Sequence analyses reveal 48-51% identity between amphibian/reptilian J chains and those of mammals, with key functional cysteines (particularly those involved in bonding) remaining invariant across these classes. Reptiles exhibit J chain genes integrated near loci, similar to mammals, supporting its evolutionary stability in sauropsids. Among cartilaginous fishes, such as , the J chain is present but specialized for IgM only, as these species lack an IgA ortholog; it is associated with pentameric IgM in plasma cells, with approximately 50% of serum IgM incorporating the chain. J chain sequences show lower overall conservation (around 30-40% identity to mammalian counterparts) but retain critical cysteines for IgM linkage, differing notably in the carboxyl-terminal region. The J chain is absent in teleost fishes (ray-finned actinopterygians), a major comprising over 30,000 species, where IgM forms tetramers via bonds alone, bypassing the need for J chain-mediated assembly. This loss likely occurred early in the actinopterygian lineage post-teleost genome duplication, as evidenced by genomic surveys showing no IGJ orthologs in species like or . However, it persists in sarcopterygian fishes, such as the African lungfish, where it co-expresses with IgM in mucosal tissues and shares 36-45% identity with sequences, including six conserved cysteines. Phylogenetic analyses of J chain sequences from jawed vertebrates, aligned across 15+ species, reveal a gnathostome origin with branching patterns mirroring vertebrate evolution: tight clustering of mammalian sequences (63-79% identity), followed by avian divergence, then conservation, and basal positioning of chondrichthyan and sarcopterygian forms. These trees highlight the actinopterygian-specific loss, with no recovery in derived clades, while invariant cysteines (e.g., those at positions 14, 44, 68 in numbering) persist across retaining taxa to preserve function.

References

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