IL13RA1 - interleukin 13 receptor subunit alpha 1 |Elisa - Clia - Antibody - Protein

Background

Interleukin-13 receptor subunit alpha-1 (IL13RA1) is a protein that serves as a primary component of the interleukin-13 receptor (IL-13R) complex, a receptor essential for immune regulation and inflammatory responses. IL13RA1, encoded by the IL13RA1 gene, is a type I cytokine receptor that primarily binds to the cytokine interleukin-13 (IL-13), a cytokine associated with type 2 helper T cell (Th2) immune responses. IL13RA1 also participates in binding interleukin-4 (IL-4), a cytokine closely related to IL-13 in function and structure, by forming a complex with IL-4 receptor alpha (IL4RA).

IL13RA1’s function in the immune system is particularly significant in responses to allergens, where it helps mediate the characteristic responses associated with allergic asthma, atopic dermatitis, and allergic rhinitis. Beyond allergy and inflammation, IL13RA1’s signaling pathways are implicated in fibrotic diseases and certain cancers, as IL-13 and IL-4 promote tissue remodeling, fibrosis, and immune modulation.

Protein Structure

IL13RA1 is a single-pass transmembrane glycoprotein that is part of the type I cytokine receptor family. The structure of IL13RA1 consists of the following domains:

Extracellular Domain:

• The extracellular domain of IL13RA1 has several key regions:
• Cytokine-Binding Region: This portion binds IL-13 with high affinity and, when in complex with IL4RA, can also bind IL-4. The binding site has a conserved arrangement typical of cytokine receptors, allowing it to recognize IL-13 and stabilize the ligand-receptor interaction.
• Fibronectin Type III (FNIII) Domains: IL13RA1 contains two FNIII domains, which provide structural support and stability. These domains are common in the cytokine receptor family and are crucial for the receptor’s conformation and cytokine-binding affinity.
• N-Linked Glycosylation Sites: IL13RA1 contains several sites for N-linked glycosylation, which contribute to the receptor’s stability and folding. Glycosylation is also essential for IL13RA1's functional surface expression, influencing receptor conformation and ligand-binding capabilities.

Transmembrane Domain:

• This single transmembrane domain spans the cellular membrane, anchoring IL13RA1 in place and positioning its extracellular domain to interact with IL-13 in the extracellular environment. The transmembrane region also stabilizes IL13RA1's interactions with IL4RA when forming the heterodimeric receptor complex.

Intracellular Domain:

• IL13RA1’s cytoplasmic domain, while relatively short, is essential for downstream signaling. Upon cytokine binding, IL13RA1 can interact with intracellular kinases, notably Janus kinase 1 (JAK1), which initiates the JAK-STAT signaling pathway. IL13RA1’s cytoplasmic tail contains motifs necessary for interacting with JAK1, which phosphorylates and activates downstream transcription factors, primarily STAT6, to propagate the immune response.

This structural organization enables IL13RA1 to form functional receptor complexes and mediate signaling pathways that are crucial for type 2 immune responses, inflammation, and tissue remodeling.

Classification and Subtypes

IL13RA1 is a member of the type I cytokine receptor family, specifically part of the class I cytokine receptor family, which includes other interleukin receptors like IL4RA and IL2RA. These receptors are characterized by their fibronectin type III domains and involvement in immune cell signaling.

Within the IL-13 receptor system, IL13RA1 does not have additional subtypes or isoforms, though it functions in cooperation with other receptors:

• IL4RA: Forms a heterodimeric complex with IL13RA1 to serve as the receptor for both IL-4 and IL-13, enabling signal transduction through the shared JAK-STAT pathways.
• IL13RA2: Another IL-13 receptor subunit that acts as a “decoy” receptor with high affinity for IL-13 but does not participate in signaling. IL13RA2 serves to regulate IL-13 activity by sequestering it, reducing the availability of IL-13 for signaling through IL13RA1.

Function and Biological Significance

The IL13RA1 receptor subunit is crucial in immune modulation, especially in the context of allergic inflammation, Th2 cell signaling, and tissue remodeling:

IL-13 and IL-4 Binding and Signal Transduction:

• IL13RA1 binds IL-13 with high affinity, either as a standalone receptor or as part of a heterodimer with IL4RA. Upon IL-13 binding, IL13RA1 associates with IL4RA to activate the JAK-STAT pathway, specifically JAK1, which subsequently phosphorylates and activates STAT6. STAT6 then translocates to the nucleus, where it promotes the transcription of target genes involved in Th2 differentiation, IgE production, and other immune responses.
• IL13RA1, in complex with IL4RA, can also bind IL-4, enabling the receptor to mediate IL-4-induced signaling events. This flexibility in ligand binding means that IL13RA1 has a dual role in responding to both IL-13 and IL-4, both of which are central to allergic and type 2 immune responses.

Role in Type 2 Immune Responses and Allergic Inflammation:

• IL13RA1 is a key mediator of Th2-type responses, which are driven by IL-13 and IL-4. These responses include the production of IgE by B cells, the activation of eosinophils, and mucus production by epithelial cells, all of which are characteristic of allergic reactions. IL13RA1 signaling supports the differentiation and maintenance of Th2 cells, facilitating responses to parasitic infections as well as allergic responses to environmental allergens.

Tissue Remodeling and Fibrosis:

• IL-13 signaling through IL13RA1 is also implicated in tissue remodeling, as IL-13 promotes the production of extracellular matrix components, including collagen, which contributes to fibrosis. Fibrosis can occur in various organs, such as the lungs, liver, and skin, as a result of chronic inflammation. In diseases such as pulmonary fibrosis and systemic sclerosis, excessive IL13RA1-mediated signaling may contribute to pathological tissue changes and organ dysfunction.

Immune Regulation and Barrier Immunity:

• IL13RA1 signaling plays a role in barrier immunity, particularly in the gut and respiratory tract, where it promotes mucus secretion and helps maintain a protective barrier against pathogens. This role is essential for preventing infection and regulating microbial communities in these tissues.

Clinical Issues

The involvement of IL13RA1 in allergic diseases, fibrosis, and other inflammatory conditions has significant clinical implications:

Allergic Diseases:

• IL13RA1 is highly relevant in allergic conditions like asthma, allergic rhinitis, and atopic dermatitis. Elevated IL13RA1 signaling in response to IL-13 and IL-4 contributes to airway hyperreactivity, mucus overproduction, and IgE synthesis, all hallmark features of asthma. Therapies targeting IL13RA1 or its ligands, IL-13 and IL-4, are being developed to reduce these symptoms and improve control over allergic diseases. Monoclonal antibodies targeting IL-13 (such as dupilumab) have shown efficacy in treating moderate to severe asthma by blocking IL-13 and IL-4 pathways.

Fibrosis:

• Chronic IL13RA1-mediated signaling is implicated in fibrosis of organs such as the lungs, liver, and skin. In idiopathic pulmonary fibrosis (IPF), for example, overactivation of IL-13 signaling pathways promotes collagen deposition and extracellular matrix production, leading to progressive lung scarring and respiratory decline. Blocking IL13RA1 or IL-13 interactions could be a potential therapeutic strategy to mitigate fibrosis.

Cancer:

• IL13RA1 is also involved in tumor immunology, particularly in cancers where IL-13 promotes an immunosuppressive microenvironment. IL-13 can facilitate tumor progression by recruiting regulatory immune cells that suppress anti-tumor immune responses. Some tumors, including certain gliomas, express IL13RA2 as a decoy to modulate IL-13 levels, but IL13RA1’s role in influencing tumor-associated inflammation is an area of research interest. Targeting IL13RA1 in the tumor microenvironment could improve anti-tumor immunity.

Autoimmune and Chronic Inflammatory Conditions:

• Dysregulated IL13RA1 signaling may contribute to chronic inflammatory diseases by promoting persistent Th2 responses. Conditions such as systemic sclerosis and eosinophilic esophagitis are associated with heightened IL-13 signaling, which contributes to inflammation and tissue remodeling. Therapeutics targeting IL-13 and IL13RA1-mediated pathways are under investigation to treat these inflammatory and fibrotic conditions.

Summary

IL13RA1 is an integral component of the IL-13 receptor system, functioning as a receptor for both IL-13 and, in complex with IL4RA, for IL-4. Structurally, IL13RA1 consists of an extracellular cytokine-binding domain with fibronectin type III repeats, a transmembrane domain, and a short cytoplasmic domain that interacts with JAK1 to initiate STAT6-mediated signaling. This signaling cascade promotes Th2-type immune responses, which are important for defense against parasites but also play a major role in allergic diseases and asthma.

Clinically, IL13RA1-mediated signaling is significant in allergic disorders, fibrotic diseases, and certain cancers, making IL13RA1 a promising target for therapeutic intervention. Treatments targeting the IL-13/IL-4 pathways are being developed to manage asthma, fibrosis, and other inflammatory conditions by inhibiting the effects of excessive IL13RA1 activation. In summary, IL13RA1 plays a critical role in immune regulation, with broad implications for health and disease, particularly in the context of allergy, fibrosis, and immune modulation in cancer.