A genetically determined molecular switch modulates the anti-inflammatory potential of human IgA

Fc receptor-driven immune system activity typically reflects a balance of activating and inhibitory mechanisms, mediated by the immunoreceptor tyrosine-based activation motif (ITAM) or inhibition motif (ITIM) in the ligand-binding alpha chain (FcγRIIa – c) or the canonical ITAM in the associated Fc...

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Published in:Frontiers in immunology Vol. 16; p. 1641351
Main Authors: Gibson, Andrew W., Wu, Jianming, Hendrickson, R. Curtis, Ptacek, Travis, Mobley, James, Edberg, Jeffrey C., Kimberly, Robert P.
Format: Journal Article
Language:English
Published: Switzerland Frontiers Media SA 2025
Frontiers Media S.A
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Agammaglobulinaemia Tyrosine Kinase - metabolism
Alleles
Antigens, CD - genetics
Antigens, CD - immunology
Antigens, CD - metabolism
Bruton's tyrosine kinase
CD89
CD89 antigen
Cloning
Cytokines
Fc receptors
FCAR
Humans
Immune system
Immunoglobulin A
Immunoglobulin A - genetics
Immunoglobulin A - immunology
Immunoglobulin A - metabolism
Immunoreceptor tyrosine-based activation motif
Immunoreceptor tyrosine-based inhibition motif
Inflammation
inhibition
Kinases
Neutrophils
Phosphorylation
Polymorphism
Proteins
Receptors, Fc - genetics
Receptors, Fc - immunology
Receptors, Fc - metabolism
Receptors, IgG - genetics
Serine
SH3BP5 (Sab)
Signal Transduction
St Louis Missouri
Grand Island
United States > US
SH3BP5 (Sab)
inhibition
signal transduction
CD89
FCAR
alleles
ISSN:1664-3224, 1664-3224
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Summary:Fc receptor-driven immune system activity typically reflects a balance of activating and inhibitory mechanisms, mediated by the immunoreceptor tyrosine-based activation motif (ITAM) or inhibition motif (ITIM) in the ligand-binding alpha chain (FcγRIIa – c) or the canonical ITAM in the associated Fc receptor γ-chain (FcRγ). A second role for the ITAM, an inhibitory role known as ITAM i , was initially recognized for the FcαRI-FcRγ signaling pair. We report an FcRγ-independent mechanism for inhibitory signaling by the IgA-binding receptor, FcαRI (CD89) in which the natural Ser 248 Gly variant in the cytoplasmic domain of the FcαRI α-chain alters the signaling capacity of FcαRI and constitutes a serine-based genetically determined switch for regulation of the anti- and proinflammatory potentials of human IgA. To elucidate the basis for this α-chain mechanism, we sought allele-specific FcαRI-associated molecules. Sab (SH3BP5), a trans-inhibitor for Bruton’s tyrosine kinase (Btk), is recruited by the more common Ser 248 allele, whereas the src-family tyrosine kinase Lyn, a Btk activator, is reciprocally recruited by the Gly 248 variant. Ser 248 phosphorylation amplifies Sab association and disrupts Lyn binding through an overlapping region containing an unconventional SH3-domain binding motif. In contrast to FcαRI Gly 248 , recruitment of Sab by FcαRI Ser 248 results in inhibition of Btk activation and suppression of IgA effector functions independent of FcRγ-pairing. Expression of a dominant-negative Sab construct releases FcαRI-mediated inhibition in a Ser 248 - allele-specific manner. These findings reveal a reversible serine-based phosphorylation-dependent molecular switch for regulation of receptor-mediated activation/inhibition that couples FcαRI α-chain to divergent inflammatory properties of human IgA.
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ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2025.1641351