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

Andrew Winston Gibson^1*Jianming Wu²R Curtis Hendrickson³Travis Ptacek¹James Mobley⁴Jeff Edberg¹Robert P Kimberly¹

• ¹Department of Medicine, University of Alabama at Birmingham, Birmingham, United States
• ²Department of Veterinary and Biomedical Sciences, University of Minnesota Twin Cities, Minneapolis, United States
• ³Department of Microbiology, University of Alabama at Birmingham, Birmingham, United States
• ⁴Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, United States

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,b and c) or the canonical ITAM in the associated Fc receptor γ-chain (FcRγ). A second role for the ITAM, an inhibitory role known as ITAMi, was initially recognized for the FcαRI-FcRγ signaling pair. We report an FcRγ-independent mechanism for inhibitory signaling by FcαRI 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 receptormediated activation/inhibition that couples FcαRI α-chain to divergent inflammatory properties of human IgA.