Phosphorylation-Mediated IFN-gamma R2 Membrane Translocation Is Required to Activate Macrophage Innate Response

As a critical step during innate response, the cytoplasmic beta subunit (IFN-gamma R2) of interferon-gamma receptor (IFN-gamma R) is induced and translocates to plasma membrane to join cc subunit to form functional IFN-gamma R to mediate IFN-gamma signaling. However, the mechanism driving membrane translocation and its significance remain largely unknown. We found, unexpectedly, that mice deficient in E-selectin, an endothelial cellspecific adhesion molecule, displayed impaired innate activation of macrophages upon Listeria monocytogcnes infection yet had increased circulating IFN-gamma. Inflammatory macrophages from E-selectin-deficient mice had less surface IFN-gamma R2 and impaired IFN-gamma signaling. BTK elicited by extrinsic E-selectin engagement phosphorylates cytoplasmic IFN-gamma R2, facilitating EFhd2 binding and promoting IFN-gamma R2 trafficking from Golgi to cell membrane. Our findings demonstrate that membrane translocation of cytoplasmic IFN-gamma R2 is required to activate macrophage innate response against intracellular bacterial infection, identifying the assembly of functional cytokine receptors on cell membrane as an important layer in innate activation and cytokine signaling.