IFNGR1 - interferon gamma receptor 1| Elisa - Clia - Antibody - Protein

Background

IFNGR1 (interferon gamma receptor 1) is an integral membrane protein that forms part of the receptor complex for interferon-gamma (IFN-γ), a cytokine critically involved in immunity, particularly in antiviral, antibacterial, and antitumor responses. IFN-γ is produced by T cells and natural killer (NK) cells and plays a role in activating macrophages, enhancing antigen presentation, and promoting the differentiation of T helper cells. The receptor for IFN-γ is a heterodimer composed of two subunits: IFNGR1 (also known as CD119), which is responsible for binding IFN-γ, and IFNGR2, which is necessary for signaling and stabilization.

The IFNGR1 gene is located on chromosome 6q23.3 and is broadly expressed in immune-related tissues such as the spleen, lymph nodes, and blood cells. The IFNGR1-IFNGR2 receptor complex activates several signaling cascades, most notably the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, to mediate the effects of IFN-γ. This receptor complex enables the transcriptional activation of various genes associated with immune response, inflammation, and cell differentiation. Mutations or deficiencies in IFNGR1 are linked to immune deficiencies, often resulting in an inability to respond effectively to infections, particularly those caused by intracellular pathogens like Mycobacterium.

Protein Structure

IFNGR1 is a type I transmembrane protein that consists of three main domains:

Extracellular Domain:

• This domain, located on the cell surface, is the main ligand-binding region for IFN-γ. It has a cytokine-binding homology module (CBM), which is composed of two fibronectin type III domains responsible for binding the cytokine.
• IFN-γ binding induces a conformational change in IFNGR1 that allows it to recruit IFNGR2, thus initiating receptor complex formation and downstream signaling.
• The extracellular domain also contains several conserved cysteine residues essential for maintaining structural integrity via disulfide bonds. These bonds stabilize the domain, helping it retain its binding capacity.

Transmembrane Domain:

• The transmembrane domain is a short, hydrophobic α-helix that anchors IFNGR1 to the cell membrane, allowing it to interact with both the extracellular cytokine and the intracellular signaling molecules.
• This domain serves as a bridge that stabilizes the extracellular and intracellular domains and ensures proper orientation within the membrane.

Intracellular Domain:

• The intracellular domain is responsible for signal transduction. It contains several critical tyrosine residues that are phosphorylated upon cytokine binding, serving as docking sites for downstream signaling proteins.
• Binding of IFN-γ to IFNGR1 results in the activation of JAK1 and JAK2, leading to phosphorylation of tyrosine residues on the receptor and subsequent recruitment of STAT1, a transcription factor that modulates gene expression.
• This domain also has sequences that interact with other signaling proteins, thereby expanding the range of IFN-γ-mediated cellular responses.

Classification and Subtypes

IFNGR1 is classified within the class II cytokine receptor family and is specifically tailored to bind IFN-γ. Unlike some other cytokine receptors, IFNGR1 does not have subtypes; rather, it exists as a single receptor protein. However, the biological functions of IFNGR1 depend on its pairing with IFNGR2, which together form the functional receptor complex for IFN-γ. Variations in the IFNGR1 gene, including point mutations or deletions, can lead to different functional outcomes, often associated with immune deficiencies.

Function and Biological Significance

IFNGR1 plays a crucial role in mediating the effects of IFN-γ, a cytokine essential for innate and adaptive immunity. The main functions and biological significance of IFNGR1 can be outlined as follows:

Activation of Macrophages and Monocytes:

• IFNGR1-mediated signaling is essential for the activation of macrophages and monocytes, enabling them to destroy intracellular pathogens, such as bacteria and viruses.
• Through activation, macrophages increase their expression of MHC class II molecules, enhancing their antigen-presenting capabilities, which is essential for adaptive immune responses.

Antigen Presentation and T Cell Activation:

• The IFNGR1-IFN-γ axis upregulates MHC class I and class II molecules on antigen-presenting cells, promoting the presentation of foreign antigens to T cells.
• This process helps activate cytotoxic T cells, which are key for targeting infected or malignant cells.

Induction of Antiviral and Antimicrobial Genes:

• Through JAK/STAT signaling, IFNGR1 upregulates a variety of antiviral and antimicrobial genes, such as inducible nitric oxide synthase (iNOS) and interferon regulatory factors (IRFs).
• These genes help cells combat viral infections and other intracellular pathogens, enhancing cellular defense mechanisms.

Modulation of Adaptive Immunity:

• IFNGR1 signaling influences T helper cell differentiation, particularly promoting Th1 differentiation, which is critical for cell-mediated immune responses.
• Th1 cells produce additional IFN-γ, creating a positive feedback loop that amplifies the immune response, especially against intracellular pathogens.

Involvement in Tumor Immunity:

• IFNGR1 and IFN-γ play roles in tumor immunity by stimulating immune cells to recognize and attack cancer cells. In some contexts, IFNGR1-mediated signaling promotes the activation of immune cells like NK cells and cytotoxic T cells that target tumors.

Clinical Issues

Mutations and deficiencies in the IFNGR1 gene can have severe clinical consequences, often resulting in increased susceptibility to infections and impaired immune responses. The main clinical conditions associated with IFNGR1 dysfunction include:

Mendelian Susceptibility to Mycobacterial Diseases (MSMD):

• MSMD is a rare genetic disorder characterized by an increased susceptibility to infections caused by mycobacteria (e.g., Mycobacterium tuberculosis and Mycobacterium avium complex) and certain other pathogens. Patients with IFNGR1 mutations often present with recurrent infections, granuloma formation, and poor inflammatory responses.
• Mutations in IFNGR1 can lead to complete or partial loss of function, with complete loss leading to severe immunodeficiency. This condition is usually inherited in an autosomal recessive manner, but some cases have autosomal dominant inheritance.

Chronic Granulomatous Disease (CGD):

• IFNGR1 dysfunction is implicated in chronic granulomatous disease, where defective IFNGR1 signaling impairs the activation of macrophages and neutrophils, resulting in defective pathogen killing.
• Patients with CGD are at higher risk of bacterial and fungal infections and may develop chronic inflammatory conditions due to the accumulation of undigested pathogens in immune cells.

Susceptibility to Viral Infections:

• Due to IFNGR1’s role in antiviral defense, individuals with IFNGR1 mutations may exhibit an increased risk of viral infections. While rare, cases have been documented where patients with IFNGR1 deficiencies experience recurrent viral infections due to compromised antiviral responses.

Autoimmune Disorders:

• Aberrant IFNGR1 signaling has been linked to certain autoimmune conditions, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These conditions are characterized by increased IFN-γ production and hyperactivation of the immune system, potentially leading to tissue damage.
• Research indicates that altered IFNGR1 signaling may contribute to the breakdown of immune tolerance, leading to an immune response against self-antigens.

Summary

The interferon-gamma receptor 1 (IFNGR1) is an essential component of the IFN-γ receptor complex and plays a crucial role in mediating immune responses against intracellular pathogens, as well as in modulating adaptive immunity and enhancing antigen presentation. Structurally, IFNGR1 is a type I transmembrane protein with an extracellular ligand-binding domain, a transmembrane domain, and an intracellular signaling domain. Through its interaction with IFNGR2, IFNGR1 initiates signaling cascades, particularly the JAK/STAT pathway, which regulates gene expression involved in immune response, inflammation, and cellular differentiation.

Clinically, mutations in IFNGR1 are associated with immunodeficiency syndromes, such as Mendelian Susceptibility to Mycobacterial Diseases (MSMD) and Chronic Granulomatous Disease (CGD), which make patients susceptible to bacterial and viral infections. Additionally, aberrant IFNGR1 signaling has been implicated in autoimmune diseases, such as lupus and rheumatoid arthritis. Understanding the function and signaling of IFNGR1 offers insights into potential therapeutic strategies for these conditions, making it a significant target in immunology and infectious disease research.