Phosphorylation-Mediated IFN-γR2 Membrane Translocation Is Required to Activate Macrophage Innate Response

Area of Science:

• Immunology
• Cell Biology
• Infectious Disease

Background:

• The interferon-gamma receptor (IFN-γR) is essential for innate immune responses, with its β subunit (IFN-γR2) translocating to the plasma membrane.
• The precise mechanisms and importance of IFN-γR2 membrane translocation remain largely uncharacterized.

Purpose of the Study:

• To elucidate the mechanism of cytoplasmic IFN-γR2 translocation to the cell membrane.
• To determine the significance of IFN-γR2 membrane translocation in macrophage activation and innate immunity against bacterial infection.

Main Methods:

• Utilized E-selectin-deficient mice and Listeria monocytogenes infection model.
• Analyzed macrophage surface IFN-γR2 expression and IFN-γ signaling.
• Investigated the role of Bruton's tyrosine kinase (BTK) and EFhd2 in IFN-γR2 trafficking.

Main Results:

• E-selectin deficiency impaired macrophage innate activation and IFN-γ signaling, with reduced surface IFN-γR2.
• E-selectin engagement induced BTK phosphorylation, which facilitated EFhd2 binding and IFN-γR2 trafficking from the Golgi to the plasma membrane.
• Circulating IFN-γ levels were increased in E-selectin-deficient mice despite impaired macrophage response.

Conclusions:

• Membrane translocation of cytoplasmic IFN-γR2 is a critical step for activating macrophage innate immunity against intracellular bacteria.
• The assembly of functional cytokine receptors on the cell membrane represents a key regulatory layer in innate activation and cytokine signaling.
• E-selectin plays a previously unrecognized role in regulating IFN-γR2 cell surface expression and macrophage function.