ITGAX - integrin subunit alpha X |Elisa - Clia - Antibody - Protein

Background

ITGAX (integrin subunit alpha X), also known as CD11c, is a gene that encodes the alpha X integrin protein. ITGAX pairs with the beta-2 integrin subunit (CD18) to form the heterodimeric receptor αXβ2, also referred to as p150,95 or complement receptor 4 (CR4). ITGAX is primarily expressed on myeloid cells, such as monocytes, macrophages, dendritic cells, and some populations of B cells and natural killer (NK) cells. This integrin is a key mediator of cell adhesion, migration, and immune surveillance, making it a critical component of the innate immune system.

The αXβ2 integrin plays a central role in several immune processes, including phagocytosis, antigen presentation, and the regulation of inflammation. The receptor binds to a variety of ligands, including complement component C3bi, ICAMs (intercellular adhesion molecules), fibrinogen, and matrix proteins such as laminin and fibronectin. Due to its crucial role in immune cell function and its involvement in various pathological conditions, ITGAX has been the subject of extensive scientific research.

Protein Structure

The ITGAX protein (CD11c) is a large transmembrane glycoprotein composed of approximately 1,160 amino acids, and it is divided into distinct structural domains, each contributing to its specific functions. Its structure is highly conserved among integrins and features critical elements that enable its adhesive and signaling capabilities.

Extracellular Region:

• The extracellular portion of ITGAX comprises more than 1,100 amino acids, representing the majority of the protein. This region is primarily responsible for ligand recognition and binding, playing a key role in interactions with various immune molecules and matrix components.
• I (inserted) domain: Like other integrins in the beta-2 subfamily, the I domain is central to ITGAX’s ligand-binding capabilities. The I domain binds to C3bi (an opsonized fragment of complement component C3) and is critical for phagocytosis and the immune response. The I domain contains a Rossmann fold and the metal ion-dependent adhesion site (MIDAS), which coordinates divalent cations (Mg²⁺, Mn²⁺). These cations are essential for stabilizing ligand binding.
• Beta-propeller domain: The N-terminal region of ITGAX consists of a seven-bladed beta-propeller structure, which works in conjunction with the I domain and the beta-2 subunit to modulate ligand specificity. This domain is also involved in interactions with other integrins and cell surface receptors.
• Thigh domain and Calf-1 and Calf-2 domains: These domains are located proximal to the transmembrane region. They help provide structural stability and are involved in the conformational changes that occur during integrin activation. These conformational changes play a critical role in switching the integrin from a low-affinity state to a high-affinity state for ligand binding.

Transmembrane Domain:

• The transmembrane region of ITGAX consists of a single alpha-helical domain that anchors the integrin to the cell membrane. This region is critical for the non-covalent dimerization between the alpha X and beta-2 (CD18) subunits, forming the functional αXβ2 integrin. The transmembrane domain also plays a role in transmitting signals between the extracellular environment and the intracellular signaling machinery.

Cytoplasmic Tail:

• The cytoplasmic domain of ITGAX is relatively short (~20 amino acids), yet it is essential for inside-out and outside-in signaling. Through interactions with cytoskeletal and signaling proteins, this region modulates integrin activation and the cytoskeletal rearrangements that are necessary for cell migration and adhesion. The cytoplasmic tail participates in bidirectional signaling, allowing for dynamic regulation of immune responses, such as cell motility, phagocytosis, and adhesion to the extracellular matrix.

Classification and Subtypes

ITGAX is part of the integrin family, a large family of cell surface receptors composed of heterodimeric complexes. Integrins are categorized based on the alpha and beta subunits they contain. ITGAX pairs with the beta-2 integrin subunit (CD18) to form the heterodimeric receptor known as αXβ2 (p150,95 or CR4). ITGAX belongs to the beta-2 integrin subfamily, which is exclusive to leukocytes.

The beta-2 integrin subfamily, also referred to as leukocyte integrins, includes four major members:

• LFA-1 (αLβ2, CD11a/CD18): Critical for T-cell activation and adhesion.
• Mac-1 (αMβ2, CD11b/CD18): Involved in phagocytosis, neutrophil migration, and immune surveillance.
• p150,95 (αXβ2, CD11c/CD18): Functions in phagocytosis, antigen presentation, and immune regulation.
• αDβ2 (CD11d/CD18): Expressed on macrophages and dendritic cells, playing a role in adhesion and migration.

Each of these integrins is specialized for different immune functions but shares a common ability to mediate cell adhesion, migration, and immune activation.

Function and Biological Significance

ITGAX, as part of the αXβ2 (CR4) integrin, performs a wide variety of functions that are critical for both innate and adaptive immunity. Some of its key roles include:

1. Phagocytosis: ITGAX plays a major role in opsonization-dependent phagocytosis. By binding to C3bi, an opsonized fragment of complement protein C3, ITGAX facilitates the recognition and engulfment of pathogens and apoptotic cells by macrophages and dendritic cells. This process is a key aspect of the innate immune response, allowing immune cells to clear pathogens and damaged cells efficiently.
2. Antigen Presentation: ITGAX is highly expressed on dendritic cells, where it plays an important role in the capture and presentation of antigens to T cells. This is a critical step in the initiation of the adaptive immune response. ITGAX-mediated interactions between dendritic cells and T cells ensure that T cells receive the necessary co-stimulatory signals to become fully activated, leading to an effective immune response.
3. Leukocyte Adhesion and Migration: ITGAX contributes to leukocyte adhesion to the vascular endothelium and extracellular matrix during inflammation. This is essential for immune cell extravasation, the process by which immune cells leave the bloodstream and migrate into tissues to combat infection or clear damaged tissue. ITGAX interacts with ligands such as ICAM-1, ICAM-2, fibrinogen, and fibronectin to mediate these adhesive interactions.
4. Immune Regulation and Inflammation: ITGAX, through its interaction with various ligands, plays a regulatory role in modulating inflammation. By promoting leukocyte adhesion and migration, it helps orchestrate the immune response during inflammation, balancing pro-inflammatory and anti-inflammatory signals. In certain contexts, ITGAX also mediates the resolution of inflammation and contributes to tissue remodeling and repair.
5. Tissue Remodeling and Repair: Beyond its role in inflammation, ITGAX is involved in tissue repair processes, particularly in wound healing and the resolution of chronic inflammation. By regulating the interaction of leukocytes with the extracellular matrix, ITGAX contributes to the restructuring and healing of damaged tissues.

Clinical Issues

Due to its significant role in immune responses, ITGAX has been implicated in a variety of clinical conditions, ranging from autoimmune diseases to chronic inflammatory disorders.

1. Autoimmune Diseases: Abnormalities in ITGAX function have been linked to autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Dysregulated ITGAX expression or signaling can lead to an overactive immune response, where the body attacks its own tissues. Genetic variants in the ITGAX gene have been associated with increased susceptibility to SLE, potentially through altered regulation of immune tolerance and inflammation.
2. Chronic Inflammatory Diseases: Overactivation of ITGAX has been observed in conditions like chronic obstructive pulmonary disease (COPD), where excessive recruitment of immune cells contributes to chronic inflammation and tissue damage. ITGAX-mediated leukocyte adhesion and migration exacerbate these inflammatory conditions by promoting the accumulation of immune cells at sites of chronic injury or infection.
3. Cancer: ITGAX has been studied in the context of tumor immunity, particularly in its role in dendritic cell function and antigen presentation. It is thought to contribute to the immune system’s ability to recognize and destroy cancer cells. However, tumors may also exploit integrin signaling pathways to evade immune surveillance, making ITGAX a potential target for cancer immunotherapy.
4. Therapeutic Targeting: Given its involvement in immune cell adhesion, migration, and phagocytosis, ITGAX is considered a potential therapeutic target for modulating immune responses. Inhibitors targeting the αXβ2 integrin could be useful in treating autoimmune diseases and inflammatory disorders by reducing the excessive recruitment and activation of immune cells.

Summary

ITGAX (integrin alpha X, CD11c) is an integral component of the immune system, where it forms the αXβ2 (CR4) integrin. This receptor is essential for phagocytosis, antigen presentation, immune cell migration, and the regulation of inflammation. ITGAX's structure includes an extensive extracellular domain for ligand binding, a transmembrane domain for membrane anchoring and dimerization, and a cytoplasmic tail that mediates signaling. ITGAX is predominantly expressed on myeloid cells, particularly dendritic cells, macrophages, and monocytes, where it orchestrates critical immune functions. Dysregulation of ITGAX activity is implicated in several autoimmune, inflammatory, and malignant diseases, making it a potential target for therapeutic interventions.