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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Vydané v:	Frontiers in immunology Ročník 16; s. 1641351
Hlavní autori:	Gibson, Andrew W., Wu, Jianming, Hendrickson, R. Curtis, Ptacek, Travis, Mobley, James, Edberg, Jeffrey C., Kimberly, Robert P.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Switzerland Frontiers Media SA 2025 Frontiers Media S.A
Predmet:	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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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2025.1641351