IL13RA2 - interleukin 13 receptor subunit alpha 2 |Elisa - Clia - Antibody - Protein

Background

Interleukin-13 receptor subunit alpha-2 (IL13RA2) is a protein encoded by the IL13RA2 gene, which functions as part of the immune system’s response to inflammation and certain immune-regulatory mechanisms. IL13RA2 is closely related to interleukin-13 receptor subunit alpha-1 (IL13RA1), both of which bind to the cytokine interleukin-13 (IL-13). However, IL13RA2 is distinctive in that it acts as a “decoy” receptor, binding IL-13 with high affinity but not actively initiating intracellular signaling, thereby modulating the effects of IL-13 on immune responses.

IL13RA2 has roles in regulating allergic reactions and fibrotic processes and is often upregulated in various pathological conditions, including certain cancers. The protein's interactions with IL-13 have implications for tissue remodeling, fibrosis, and immune regulation, making it an important target in the fields of immunology, oncology, and fibrosis research.

Protein Structure

IL13RA2 is a single-pass transmembrane glycoprotein that belongs to the type I cytokine receptor family. The protein structure of IL13RA2 comprises the following components:

Extracellular Domain:

• The extracellular domain of IL13RA2 contains a highly specific cytokine-binding region that binds IL-13 with high affinity, often even greater than IL13RA1. This domain includes conserved fibronectin type III (FNIII) domains, which are essential for stabilizing the ligand-receptor complex and ensuring high-affinity binding.
• Glycosylation Sites: The extracellular region contains multiple N-linked glycosylation sites that are essential for proper protein folding, receptor stability, and efficient ligand binding. Glycosylation plays a role in modulating the receptor's localization to the cell surface and its interaction with IL-13.

Transmembrane Domain:

• IL13RA2 possesses a single transmembrane helix that anchors the receptor to the cell membrane. This transmembrane domain is crucial for positioning the extracellular ligand-binding domain in an optimal orientation for capturing IL-13 from the surrounding environment.

Intracellular Domain:

• Unlike many other cytokine receptors, IL13RA2 has a very short cytoplasmic tail that lacks the typical signaling motifs. Due to this, IL13RA2 does not engage in traditional intracellular signaling upon ligand binding. Instead, its role is to act as a decoy receptor, sequestering IL-13 and preventing it from binding to other receptors like IL13RA1, which would otherwise lead to downstream immune responses.

IL13RA2’s structure enables it to act primarily as a “scavenger” for IL-13, helping to fine-tune the immune response and prevent excessive inflammatory signaling.

Classification and Subtypes

IL13RA2 belongs to the type I cytokine receptor family and is classified specifically within the interleukin-13 receptor system. Unlike IL13RA1, which pairs with interleukin-4 receptor alpha (IL4RA) to transmit signals, IL13RA2 does not possess signaling capabilities due to its truncated cytoplasmic domain. There are no distinct isoforms or subtypes of IL13RA2 reported, but its expression varies across tissue types, including immune cells, fibroblasts, and epithelial cells.

Function and Biological Significance

The primary function of IL13RA2 is to serve as a decoy receptor for IL-13, effectively modulating the activity of this cytokine in the immune system:

IL-13 Binding and Decoy Activity:

• IL13RA2 binds IL-13 with a higher affinity than IL13RA1, but it does not engage in intracellular signaling. By binding IL-13, IL13RA2 prevents the cytokine from interacting with signaling receptors, thereby modulating the magnitude of IL-13-induced responses. This decoy function is particularly important in regulating immune responses and controlling the effects of IL-13 on allergic inflammation and fibrosis.

Role in Allergic Inflammation:

• IL-13 is central to type 2 helper T cell (Th2) responses, which are involved in allergic reactions, asthma, and other immune conditions. By sequestering IL-13, IL13RA2 reduces its availability for binding to IL13RA1/IL4RA receptor complexes, which in turn decreases downstream activation of STAT6, a transcription factor essential for Th2 differentiation, IgE production, and mucus secretion. This modulation helps to prevent excessive Th2 responses, which could lead to severe allergic reactions or chronic inflammation.

Role in Fibrosis and Tissue Remodeling:

• IL13RA2 has been implicated in the development of fibrosis, a process where tissue repair mechanisms become dysregulated, leading to excessive deposition of extracellular matrix components like collagen. Fibrosis can result in organ dysfunction over time. IL13RA2’s regulation of IL-13 availability affects fibrogenic responses in organs such as the lungs, liver, and kidneys. In conditions like idiopathic pulmonary fibrosis and systemic sclerosis, increased IL-13 activity promotes fibroblast proliferation and collagen deposition. IL13RA2’s ability to modulate IL-13 levels suggests it plays a significant role in controlling fibrotic processes.

Role in Cancer:

• IL13RA2 is often overexpressed in various cancers, including glioblastoma, melanoma, and pancreatic cancer. While IL13RA2 does not signal directly, its binding to IL-13 in the tumor microenvironment can promote tumor growth, possibly by suppressing local immune responses or by interacting with other receptors in ways that favor tumor survival and invasion. IL13RA2’s unique expression in some cancers makes it a target for immunotherapy and other cancer treatments. For instance, chimeric antigen receptor (CAR) T-cell therapies targeting IL13RA2 have been explored for glioblastoma, as the receptor is highly expressed in this tumor type but limited in normal brain tissue.

Clinical Issues

The clinical significance of IL13RA2 is evident in several disease contexts:

Asthma and Allergic Diseases:

• IL13RA2’s regulation of IL-13 availability has implications for allergic diseases such as asthma and atopic dermatitis. Increased IL13RA2 expression has been associated with milder disease phenotypes, as the receptor limits IL-13-driven inflammation and Th2 cell activity. Modulating IL13RA2 expression or enhancing its decoy function could be a therapeutic approach in treating allergic diseases by limiting IL-13’s pro-inflammatory effects.

Fibrotic Diseases:

• Given IL13RA2’s role in modulating IL-13-mediated fibrosis, it is a potential therapeutic target in conditions like idiopathic pulmonary fibrosis (IPF), liver fibrosis, and systemic sclerosis. Enhancing IL13RA2 activity in fibrotic tissues could reduce IL-13-induced collagen production and tissue remodeling, slowing disease progression. Current research is exploring IL13RA2-based therapies as a means of controlling fibrosis, as well as other molecular inhibitors that target the IL-13 pathway.

Cancer Therapeutics:

• IL13RA2 is overexpressed in glioblastoma and other cancers, where it aids in immune evasion and tumor progression. Its selective expression in tumors over normal tissues makes IL13RA2 an attractive target for cancer therapies. For example, CAR T-cell therapies have been engineered to target IL13RA2, aiming to deliver cytotoxic activity specifically to tumor cells that overexpress this receptor. Additionally, IL13RA2-directed antibodies and inhibitors are under investigation as potential therapies for cancers that express high levels of IL13RA2.

Autoimmune and Chronic Inflammatory Conditions:

• IL13RA2’s role in controlling IL-13 activity could have therapeutic relevance in autoimmune diseases where excessive Th2 activity contributes to inflammation and tissue damage. By regulating IL-13’s availability, IL13RA2 can help balance immune responses, potentially offering a therapeutic approach for conditions such as eosinophilic esophagitis and systemic lupus erythematosus.

Summary

IL13RA2 is a critical modulator in the IL-13 receptor system, acting as a high-affinity decoy receptor for IL-13 without initiating downstream signaling. Structurally, IL13RA2 is a single-pass transmembrane protein with an extracellular cytokine-binding domain containing fibronectin type III repeats and a truncated cytoplasmic domain that lacks signaling capacity. This unique structure allows IL13RA2 to sequester IL-13, modulating immune and inflammatory responses.

The biological significance of IL13RA2 is apparent in its role in allergic responses, fibrosis, and cancer. By reducing the availability of IL-13 for signaling, IL13RA2 helps control type 2 immune responses, including Th2 differentiation and IgE production, which are essential for allergic inflammation. In fibrosis, IL13RA2’s regulation of IL-13 activity can reduce excessive tissue remodeling and collagen deposition. In the context of cancer, IL13RA2 is often overexpressed and supports tumor growth by modulating the immune microenvironment, making it a promising target for therapies like CAR T-cells.

In conclusion, IL13RA2’s function as a decoy receptor for IL-13 positions it as an essential regulator of immune responses, with broad implications in asthma, fibrosis, and cancer therapy. Targeting IL13RA2 for therapeutic modulation of IL-13 activity holds potential for treating a variety of chronic diseases.