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

Date Published: 2025-08-27

Abstract:
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 (Fc?RIIa – c) or the canonical ITAM in the associated Fc receptor ?-chain (FcR?). A second role for the ITAM, an inhibitory role known as ITAM i , was initially recognized for the Fc?RI-FcR? signaling pair. We report an FcR?-independent mechanism for inhibitory signaling by the IgA-binding receptor, Fc?RI (CD89) in which the natural Ser 248 Gly variant in the cytoplasmic domain of the Fc?RI ?-chain alters the signaling capacity of Fc?RI 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 ?-chain mechanism, we sought allele-specific Fc?RI-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 Fc?RI Gly 248 , recruitment of Sab by Fc?RI Ser 248 results in inhibition of Btk activation and suppression of IgA effector functions independent of FcR?-pairing. Expression of a dominant-negative Sab construct releases Fc?RI-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 Fc?RI ?-chain to divergent inflammatory properties of human IgA.

Introduction:
The Fc?RI protein (CD89) binds to its cognate ligands, IgA and C-reactive protein (CRP), and can interact directly with both gram-positive and gram-negative bacterial species. This binding mediates effector functions ( 1 , 2 ). Fc?RI is expressed constitutively on myeloid cells, including neutrophils, monocytes, macrophages, eosinophils, and a subpopulation of dendritic cells ( 1 , 3 – 5 ). The receptor is also expressed on Kupffer cells, where it is thought to play a role in IgA nephropathy ( 6 ). Structurally,…

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