IFNGR1

IFNGR1, or interferon gamma receptor 1, is the alpha subunit of the type II interferon receptor. It binds interferon-gamma (IFN-γ) and, together with the beta subunit IFNGR2, forms the high-affinity receptor for IFN-γ. The IFNGR1 protein is a single-pass transmembrane glycoprotein with an extracellular ligand-binding domain and a cytoplasmic signaling tail that participates in transmitting the signal downstream.

IFNGR1 forms a heterodimer with IFNGR2 to create the functional IFN-γ receptor complex. Upon IFN-γ binding, associated Janus kinases are activated (JAK1 linked to IFNGR1 and JAK2 linked to IFNGR2), leading to phosphorylation and activation of the transcription factor STAT1. Phosphorylated STAT1 dimerizes, translocates to the nucleus, and stimulates transcription of IFN-γ–responsive genes through gamma-activated sequence elements. This signaling cascade induces antimicrobial, immunomodulatory, and antigen-presenting programs.

Expression of IFNGR1 is widespread, with prominent presence on immune cells such as macrophages, dendritic cells, T cells, and B cells, and detectable levels in many other tissues. Its expression can be modulated by inflammatory stimuli, enabling a rapid response to intracellular pathogens.

Genetically, IFNGR1 is subject to mutations that impair IFN-γ signaling, causing Mendelian susceptibility to mycobacterial disease (MSMD). Mutations can be autosomal recessive or dominant and may result in reduced surface expression or defective signaling, varying in clinical severity. Diagnosis typically involves genetic testing and functional assays of the IFN-γ pathway. Treatment strategies focus on infection control and, in severe cases, may include therapies that augment IFN-γ–mediated responses.