Structural Requirements for the Interaction of Human IgA with the Human Polymeric Ig Receptor

Lewis, Melanie J.; Pleass, Richard J.; Batten, Margaret R.; Atkin, Julie D.; Woof, Jenny M.

doi:10.4049/jimmunol.175.10.6694

Cited by 44 publications

(61 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Intracellular virion-associated IgA molecules are recognized by the cytosolic antibody receptor TRIM21, stimulating both ADIN and innate immune signaling. Serum IgA antibodies of both subclasses (IgA1 and IgA2) bind TRIM21 with similar affinity, consistent with the fact that they share the same TRIM21 epitope sequence (PLAF motif) and previous studies showing that they interact equally with pIgR (15). Secretory IgA shows reduced binding to TRIM21, presumably as a consequence of the secretory chain; however, under reducing conditions, a similar binding affinity to TRIM21 as serum IgA is observed.…”

Section: Discussionsupporting

confidence: 88%

“…For example, in the case of HIV, transcytosing IgA meets endocytosed HIV particles in the apical recycling endosome, whereupon the virus is bound and secreted back out into the lumen with the IgA (31). The mechanism of this type of intracellular neutralization is not fully understood; however, it is unlikely to involve TRIM21 as transcytosing IgA is not thought to become cytoplasmically accessible and because pIgR binding to Fcα would be predicted to occlude TRIM21 binding (15). Nevertheless, our data support growing evidence that IgA antibodies play a significant role in antiviral immunity.…”

Section: Discussionmentioning

confidence: 99%

“…Of these, one neutralized infection independently of TRIM21, whereas in the other, depletion of TRIM21 partially rescued infection. The ability of TRIM21 to use S-IgA was surprising given that the SC binding site overlaps TRIM21 (15), although the SC is not thought to engage both heavy chains in each IgA monomer (16). In fluorescence titration experiments, an increase in anisotropy was observed on addition of S-IgA to TRIM21 PRYSPRY, but a sufficiently high concentration of antibody could not be reached to determine affinity ( serum IgA data suggests that the presence of the SC is inhibitory to TRIM21 binding of IgA.…”

Section: Significancementioning

confidence: 99%

“…In turn, the weaker binding affinity may be the reason why IgA-mediated ADIN is less efficient than IgG-mediated ADIN. Interestingly, the Fcα PLAF loop is critical in mediating interactions with multiple proteins including the human Fc receptors FcαRI, Fcα/μR, the polymeric Ig receptor (pIgR), the pathogenproduced antigens SSL7 from Staphylococcus aureus, M proteins, Sir22, and ARP4 from group A streptococci, β-protein from group B streptococci, and the type 2 IgA1 protease produced by Neisseria meningitidis (15,19,(22)(23)(24)(25)(26)(27). Unlike TRIM21, however, these IgA receptors are more isotype specific (although Fcα/μR interacts with both IgA and IgM).…”

Section: Trim21 Uses a Degenerate Binding Mechanism To Bind Iga Igmmentioning

confidence: 99%

See 3 more Smart Citations

Translocalized IgA mediates neutralization and stimulates innate immunity inside infected cells

Bidgood

Tam

McEwan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

IgA is the most prevalent antibody type on mucosal surfaces and the second most prevalent antibody in circulation, yet its role in immune defense is not fully understood. Here we show that IgA is carried inside cells during virus infection, where it activates intracellular virus neutralization and innate immune signaling. Cytosolic IgA-virion complexes colocalize with the high-affinity antibody receptor tripartite motif-containing protein 21 (TRIM21) and are positive for lysine-48 ubiquitin chains. IgA neutralizes adenovirus infection in a TRIM21-and proteasome-dependent manner in both human and mouse cells. Translocated IgA also potently activates NF-κB signaling pathways in cells expressing TRIM21, whereas viral infection in the absence of antibody or TRIM21 is undetected. TRIM21 recognizes an epitope in IgG Fc that is not conserved in IgA; however, fluorescence anisotropy experiments demonstrate that direct binding to IgA is maintained. We use molecular modeling to show that TRIM21 forms a nonspecific hydrophobic seal around a β-loop structure that is present in IgG, IgM, and IgA, explaining how TRIM21 achieves such remarkable broad antibody specificity. The findings demonstrate that the antiviral protection afforded by IgA extends to the intracellular cytosolic environment.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Trim21 Uses a Degenerate Binding Mechanism To Bind Iga Igmmentioning

confidence: 99%

See 2 more Smart Citations

Translocalized IgA mediates neutralization and stimulates innate immunity inside infected cells

Bidgood

Tam

McEwan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In IgA, the C␣2/C␣3 junction appears to be a hot spot for recognition by diverse molecules such as SSL7, Fc␣RI (CD89) (24,26,27), as well as proteins from group A streptococci (M proteins; Sir22/Arp4), group B streptococci (␤-protein) (29,30), and it forms part of the human polymeric Ig receptor-binding site (31). The C␥2/C␥3 domain junction of IgG is also a target site for multiple binding proteins, including the neonatal Fc receptor (32), staphylococcal protein A (25), autoantibodies or rheumatoid factors (33), viral receptors (34), and Trim21 or Ro52 (35).…”

Section: Discussionmentioning

confidence: 99%

Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1

Ramsland

Willoughby

Trist

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

106

102

View full text Add to dashboard Cite

Infection by Staphylococcus aureus can result in severe conditions such as septicemia, toxic shock, pneumonia, and endocarditis with antibiotic resistance and persistent nasal carriage in normal individuals being key drivers of the medical impact of this virulent pathogen. In both virulent infection and nasal colonization, S. aureus encounters the host immune system and produces a wide array of factors that frustrate host immunity. One in particular, the prototypical staphylococcal superantigen-like protein SSL7, potently binds IgA and C5, thereby inhibiting immune responses dependent on these major immune mediators. We report here the three-dimensional structure of the complex of SSL7 with Fc of human IgA1 at 3.2 Å resolution. Two SSL7 molecules interact with the Fc (one per heavy chain) primarily at the junction between the C␣2 and C␣3 domains. The binding site on each IgA chain is extensive, with SSL7 shielding most of the lateral surface of the C␣3 domain. However, the SSL7 molecules are positioned such that they should allow binding to secretory IgA. The key IgA residues interacting with SSL7 are also bound by the leukocyte IgA receptor, Fc␣RI (CD89), thereby explaining how SSL7 potently inhibits IgAdependent cellular effector functions mediated by Fc␣RI, such as phagocytosis, degranulation, and respiratory burst. Thus, the ability of S. aureus to subvert IgA-mediated immunity is likely to facilitate survival in mucosal environments such as the nasal passage and may contribute to systemic infections.Staphylococcus aureus is an important human pathogen causing conditions ranging from minor superficial skin infections to life-threatening syndromes, including sepsis, toxic shock syndrome, osteomyelitis, pneumonitis, and endocarditis. It is carried without symptoms in at least 20% of individuals (1, 2). The emergence in the 1960s of pandemic penicillin-resistant S. aureus has been followed by a variety of hospital-associated and community-associated methicillin-resistant strains (HA-and CA-MRSA) (2, 3). The increased prevalence of MRSA infections and corresponding rise in life-threatening syndromes have made it imperative to elucidate the mechanisms of pathogenesis for S. aureus. The interaction between S. aureus and the host is complex and is mediated by an array of bacterial proteins that both mediate the various pathologies and modify the immune system of the host (4-10).SSL7 (formerly named SET1) is the first described member of a new family of putative S. aureus toxins, the staphylococcal superantigen-like (SSL) proteins (11, 12), related to the staphylococcal enterotoxins (SEs) or superantigens (13). The SSL proteins have Ϸ30% sequence identity with toxic shock syndrome 1 (TSST-1) and 25% or less identity with other SEs. Despite the sequence differences, the SSL proteins have a typical SE tertiary structure consisting of a distinct oligonucleotide/oligosaccharide binding (OB-fold) linked to a ␤-grasp domain (14 -16).Similar to the se genes, the ssl genes are located in a pathogenicity island (SaPIn2) and ...

show abstract

Structural requirements for the interaction of human IgM and IgA with the human Fcα/μ receptor

et al. 2009

Self Cite

View full text Add to dashboard Cite

Here we unravel the structural features of human IgM and IgA that govern their interaction with the human Fca/l receptor (hFca/lR). Ligand polymerization status was crucial for the interaction, because hFca/lR binding did not occur with monomeric Ab of either class. hFca/lR bound IgM with an affinity in the nanomolar range, whereas the affinity for dimeric IgA (dIgA) was tenfold lower. Panels of mutant IgM and dIgA were used to identify regions critical for hFca/lR binding. IgM binding required contributions from both Cl3 and Cl4 Fc domains, whereas for dIgA, an exposed loop in the Ca3 domain was crucial. This loop, comprising residues Pro440-Phe443, lies at the Fc domain interface and has been implicated in the binding of host receptors FcaRI and polymeric Ig receptor (pIgR), as well as IgA-binding proteins produced by certain pathogenic bacteria. Substitutions within the Pro440-Phe443 loop resulted in loss of hFca/lR binding. Furthermore, secretory component (SC, the extracellular portion of pIgR) and bacterial IgA-binding proteins were shown to inhibit the dIgA-hFca/lR interaction. Therefore, we have identified a motif in the IgA-Fc inter-domain region critical for hFca/lR interaction, and highlighted the multi-functional nature of a key site for protein-protein interaction at the IgA Fc domain interface.Key words: Human Fca/m receptor . IgA . IgM IntroductionA receptor for IgM and IgA, termed Fca/m receptor (Fca/mR), was first described in the mouse where it is constitutively expressed on the majority of B cells and macrophages [1]. Mouse Fca/mR (mFca/mR) can mediate endocytosis of IgM-coated targets, and may contribute to the primary stages of the immune response to microbes. It has been suggested that mFca/mR, due to its high affinity for IgM and intermediate affinity for IgA, may assist also in the maintenance of plasma concentrations of IgM and IgA [2]. Although there is no significant homology between Fca/mR and other known proteins, the N-terminal Ig-like domain of Fca/mR Ã These authors contributed equally to this work. Certain mAb raised against mFca/mR have been found to bind to a peptide encompassing the region from mFca/mR's Ig-like domain that corresponds to the Ig-binding motif in domain 1 of pIgR [6]. Interestingly, these mAb can block binding of IgA and IgM to mFca/mR. The fact that these same mAb cross-react with hFca/mR, which carries the conserved motif in its Ig-like domain, suggests that the site for IgM and IgA on hFca/mR lies in this same region. In contrast, the site(s) on human IgM and IgA that interacts with hFca/mR is unknown. To gain a better understanding of the structural requirements for the interaction of human IgA and IgM with hFca/mR, we have produced recombinant dIgA and pentameric IgM and have adopted a mutational approach to identify individual residues on the Fc involved in interaction with hFca/mR. We demonstrate that both the Cm3 and Cm4 domains of IgM are required for binding to the receptor, and that residues at the Fc inter-domain region of dIgA are critical for hFca...

show abstract

Structural Requirements for the Interaction of Human IgA with the Human Polymeric Ig Receptor

Cited by 44 publications

References 62 publications

Translocalized IgA mediates neutralization and stimulates innate immunity inside infected cells

Translocalized IgA mediates neutralization and stimulates innate immunity inside infected cells

Structural basis for evasion of IgA immunity by Staphylococcus aureus revealed in the complex of SSL7 with Fc of human IgA1

Structural requirements for the interaction of human IgM and IgA with the human Fcα/μ receptor

Contact Info

Product

Resources

About