IFNGR1: The gating subunit of the IFN-γ signaling pathway and a key molecule in macrophage antimicrobial immunity

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This article systematically elucidates the central role of IFN-γR1 (IFNGR1) as the constitutive binding subunit of the IFN-γ signaling pathway in the antimicrobial immunity of macrophages, focusing on the composition and function of the type II interferon receptor. It also analyzes the molecular mechanism by which IFN-γR2 translocates from the cytoplasm to the cell membrane under infectious conditions and its decisive role in the assembly of functional receptors.

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IFNGR1: The Gatekeeper Subunit of IFN-γ Signaling Pathway and a Key Molecule in Macrophage Antimicrobial Immunity

Summary
This article systematically elaborates on the composition and function of the type II interferon receptor, focusing on the central role of IFN-γR1 (IFNGR1) as the constitutive binding subunit of the IFN-γ signaling pathway in macrophage antimicrobial immunity. It also analyzes the molecular mechanism of IFN-γR2 translocation from the cytoplasm to the cell membrane under infection conditions and its decisive role in the assembly of functional receptor complexes.

I. Molecular Composition of Type II Interferon and IFN-γ Receptor

Under the stimulation of pathogenic microorganisms, the host's innate immune system senses invading pathogens and activates immune responses, producing interferons and various cytokines. In mammals, the interferon family can be divided into type I, type II, and type III, with type II interferon IFN-γ widely involved in immune and inflammatory responses. IFN-γ activates intracellular signaling pathways through the JAK/STAT pathway, inducing the expression of downstream genes and playing a central role in promoting macrophage activation, mediating host defense against pathogens, and regulating anti-tumor immunity. Therefore, the normal function of the IFN-γ signaling pathway depends on the IFN-γ receptor expressed on the cell surface, and the mechanism of its expression and aggregation on the membrane has long been an important research topic in the field.

The functional IFN-γ receptor consists of two subunits: IFN-γ receptor α (IFN-γR1, also known as IFNGR1) and IFN-γ receptor β (IFN-γR2, also known as IFNGR2). These two subunits differ significantly in expression patterns and functional分工: IFN-γR1 is constitutively expressed on the surface of nucleated cells and is primarily responsible for binding the IFN-γ ligand; IFN-γR2 translocates from the cytoplasm to the cell membrane after bacterial infection, inducibly expressed on the cell surface, and assembles with IFN-γR1 to form a functional receptor complex. The expression of IFN-γR2 in immune cells is cell-type specific—higher in myeloid cells and B cells, and lower or even absent in T cells. In macrophages, IFN-γ does not affect the expression level of IFN-γR2; glycosylated IFN-γR2 can regulate the IFN-γ signaling pathway by influencing dynamic interactions with actin and lipid domains. Abnormal expression of IFN-γR1 and IFN-γR2 is closely related to the occurrence of Mendelian susceptibility to mycobacterial disease, further highlighting the critical role of this receptor system in immune defense.

II. E-selectin-Mediated Mechanism of IFN-γR2 Membrane Translocation

New research has found that in E-selectin-deficient mice infected with Listeria, serum IFN-γ levels were abnormally elevated, but the expression of IFN-γR2 on the macrophage cell membrane was significantly reduced, and the IFN-γ signaling pathway was inhibited. Mechanistically, E-selectin regulates the phosphorylation of cytoplasmic IFN-γR2 by BTK kinase, promoting its binding to Efhd2 and facilitating the translocation of IFN-γR2 from the Golgi apparatus to the cell membrane, thereby activating macrophage immune responses to bacterial infection. In E-selectin knockout mice, although the total protein level of IFN-γR2 remained unchanged, its localization on the cell membrane was significantly reduced, indicating that E-selectin is indispensable for the membrane expression of IFN-γR2. Further studies revealed that CCR2⁺ migratory macrophages exhibited more pronounced loss of IFN-γR2 membrane expression after infection, suggesting a key regulatory role of E-selectin in this specific macrophage subset.

III. Molecular Pathway of IFN-γR2 Translocation Driven by the BTK-Efhd2 Axis

From a signaling perspective, the binding of endothelial cell E-selectin to its leukocyte ligand activates the SYK and BTK kinase signaling pathways. In this signaling axis, BTK, as the primary downstream signal molecule of SYK, mediates the translocation of IFN-γR2 in macrophages—BTK-deficient mice showed reduced IFN-γR2 membrane expression after Listeria stimulation, while overexpression of BTK protein significantly restored IFN-γR2 membrane expression in E-selectin knockout macrophages. This process relies on the direct phosphorylation of IFN-γR2 at tyrosine 289 by BTK, promoting the translocation of IFN-γR2 from the Golgi apparatus to the cell membrane.

Efhd2, another key molecule, participates in the translocation process of IFN-γR2. Efhd2 contains two EF-hand domains that bind Ca²⁺ and mediate immune cell activation. Mass spectrometry identified Efhd2 as an interaction partner of IFN-γR2, and in vitro experiments confirmed that Efhd2 could bind wild-type IFN-γR2 under BTK action but not the IFN-γR2 Y289A mutant. EFhd2-deficient mice exhibited abnormally elevated serum IFN-γ levels and significantly reduced IFN-γR2 membrane expression on macrophages after Listeria stimulation. This evidence establishes the complete molecular pathway of "BTK phosphorylation of IFN-γR2—EFhd2 binding—Golgi to membrane translocation."

IV. Conclusion

IFNGR1, as the constitutive binding subunit of the IFN-γ receptor, assembles with inducibly expressed IFN-γR2 to form a functional receptor complex, serving as the gatekeeper molecule for the initiation of the IFN-γ signaling pathway. The research by Cao Xuetao's team systematically elucidated the key signaling events of IFN-γR2 synthesis in the endoplasmic reticulum, phosphorylation by BTK, and EFhd2-mediated translocation to the cell membrane, providing the first evidence that vascular endothelial cells can pre-regulate macrophages migrating to inflammatory sites through E-selectin in an inflammatory environment. These findings offer new perspectives for understanding how interaction signals between host cells and innate immune cells regulate cytokine receptor expression and lay the foundation for research on cytokine and functional receptor interactions in autoimmune disease treatment and anti-tumor immunity applications.

In the mechanistic study of the IFN-γ signaling pathway, high-quality recombinant IFNGR1 protein is a core tool for receptor-ligand binding analysis, signal transduction research, and antibody screening. To meet this research need, Uni offers IFN-gamma R1/IFNGR1 Fc Chimera Protein, Human, suitable for IFN-γ and IFNGR1 binding activity analysis, IFN-γ signaling pathway blockade studies, and in vitro activity evaluation of antibodies or fusion protein drugs targeting IFNGR1.

This article is reviewed and published by the technical expert team of UA

Disclaimer: This article partially utilizes artificial intelligence assistance in its creation. If any content involves copyright or intellectual property issues, please let us know and we promise to verify and remove it as soon as possible.

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