Inside-out regulation of FcαRI (CD89) depends on PP2A

To achieve a correct cellular immune response toward pathogens, interaction between FcR and their ligands must be regulated. The Fc receptor for IgA, Fc alpha RI, is pivotal for the inflammatory responses against IgA-opsonized pathogens. Cytokine-induced inside-out signaling through the intracellular FcaRI tail is important for F alpha aRI-IgA binding. However, the underlying molecular mechanism governing this process is not well understood. In this study, we report that PP2A can act as a molecular switch in Fc alpha RI activation. PP2A hinds to the intracellular tail of FcaRI and, upon cytokine stimulation, PP2A becomes activated. Subsequently, Fc alpha RI is dephosphorylated on intracellular Serine 263, which we could link to receptor activation. PP2A inhibition, in contrast, decreased FcaRI ligand binding capacity in transfected cells but also in eosinophils and monocytes. Interestingly, PP2A activity was found crucial for IgA-mediated binding and phagocytosis or Neisseria meningitidis. The present findings demonstrate MA involvement as a molecular mechanism for FcaRI ligand binding regulation, a key step in initiating an immune response.