IL3RA - interleukin 3 receptor subunit alpha | Elisa - Clia - Antibody - Protein

Background

IL3RA, also known as CD123, encodes the alpha subunit of the interleukin-3 (IL-3) receptor, an essential receptor in hematopoiesis and immune cell regulation. IL3RA pairs with the common beta subunit (CSF2RB or IL3RB) to form the functional receptor complex for IL-3, a cytokine primarily involved in the growth, differentiation, and survival of various blood cell lineages. The IL-3 receptor is primarily expressed on hematopoietic progenitor cells and is particularly prominent on cells within the myeloid lineage, including basophils, eosinophils, and certain dendritic cells.

IL3RA’s role in hematopoiesis is critical as it contributes to regulating immune responses by driving differentiation and survival of blood cell progenitors. The receptor is also crucial in mobilizing immune cells, promoting proliferation and enhancing responses to infection. IL3RA’s clinical significance has grown in recent years, with elevated expression observed in leukemias, particularly in acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Its surface expression profile has made IL3RA an important therapeutic target, especially in cancers where IL3RA-positive cells drive disease progression.

Protein Structure

IL3RA has a distinct protein structure that allows it to specifically bind IL-3 and interact with the beta subunit for signal transduction. The structural domains of IL3RA are organized as follows:

Extracellular Domain (ECD):

• The ECD of IL3RA is composed of approximately 305 amino acids and includes two distinct cytokine receptor homology (CRH) domains that contribute to IL-3 binding and receptor specificity.
• Within the ECD, fibronectin type III (FNIII)-like domains are critical for ligand interaction. These FNIII domains contain specific residues that make contact with IL-3, stabilizing the ligand-receptor binding complex.
• The ECD is glycosylated, with N-linked glycosylation sites that enhance protein folding and stability, potentially affecting receptor affinity for IL-3.

Transmembrane Domain (TMD):

• The TMD anchors IL3RA to the plasma membrane and is crucial for positioning the extracellular domain in the cell membrane for optimal ligand interaction. It consists of a single alpha-helical transmembrane segment that links the ECD with the intracellular domain.

Intracellular Domain (ICD):

• The ICD of IL3RA is relatively short compared to other cytokine receptors, lacking intrinsic signaling capabilities, which makes it reliant on interaction with the beta subunit (CSF2RB) for downstream signaling.
• Upon IL-3 binding, conformational changes in IL3RA facilitate recruitment and activation of CSF2RB, which then initiates signal transduction through various downstream pathways, including JAK-STAT, MAPK/ERK, and PI3K/AKT pathways.
• Specific phosphorylation sites on the beta subunit, once activated, recruit additional signaling proteins, which leads to gene transcription, cellular proliferation, and survival.

Classification and Subtypes

IL3RA belongs to the type I cytokine receptor family, specifically within the hematopoietin receptor superfamily. This family is characterized by a conserved sequence within their extracellular domains that enables them to bind various cytokines involved in immune modulation and hematopoiesis. IL3RA, together with CSF2RB, forms the high-affinity receptor for IL-3, and, similar to IL5RA and CSF2RA, it utilizes the shared beta subunit for signaling.

There are no known subtypes of IL3RA; however, it is expressed differently among cell types and stages of hematopoietic differentiation. Its expression profile is particularly significant in distinguishing hematopoietic stem cells and leukemic blasts in AML, where IL3RA is often highly expressed, aiding in the diagnosis and prognosis of certain hematologic malignancies.

Function and Biological Significance

IL3RA is integral to hematopoiesis and immune regulation. It has the following key functions and biological roles:

Hematopoietic Regulation:

• IL3RA mediates IL-3-dependent proliferation and differentiation of hematopoietic progenitor cells into various blood lineages, particularly myeloid cells. This includes eosinophils, basophils, mast cells, and other immune cells involved in allergic responses and pathogen defense.
• IL-3 binding to IL3RA initiates signals that drive proliferation and differentiation within the bone marrow, supporting steady-state hematopoiesis and the replenishment of blood cells.

Immune Cell Survival and Activation:

• IL-3 signaling through IL3RA plays a pivotal role in the survival and activation of immune cells, particularly during infections and allergic responses. In dendritic cells and basophils, IL3RA enhances cytokine production, antigen presentation, and cell survival.
• The signaling cascade activated by IL3RA modulates immune cell lifespan, increasing the availability of immune effectors during immune challenges.

Role in Allergy and Inflammation:

• IL3RA expression on basophils and eosinophils suggests a significant role in allergic inflammation. IL-3 is known to enhance these cells’ survival and cytokine production, which contributes to inflammatory responses in conditions like asthma and allergic rhinitis.
• The receptor’s activation can lead to upregulation of pro-inflammatory cytokines, enhancing immune cell recruitment and amplifying allergic responses, making it an area of interest in allergy treatment research.

Cancer Progression and Maintenance:

• IL3RA is expressed at high levels in acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). In these malignancies, IL-3 signaling promotes leukemic cell survival and proliferation, supporting tumor maintenance and progression.
• IL3RA serves as a diagnostic and prognostic marker in AML and BPDCN. Its expression on leukemic blasts enables targeted therapeutic strategies aimed at depleting IL3RA-positive cells, potentially reducing disease progression.

Clinical Issues

Due to its expression pattern and role in hematologic diseases, IL3RA is linked to several clinical conditions and is a target for therapeutic interventions:

Acute Myeloid Leukemia (AML):

• IL3RA is overexpressed on leukemic blasts in AML, where it is implicated in cell proliferation and resistance to apoptosis. Targeting IL3RA in AML has become a potential therapeutic strategy, with drugs such as tagraxofusp, a CD123-directed cytotoxin, showing promise in treating IL3RA-expressing malignancies.
• The receptor serves as a biomarker for AML, aiding in distinguishing leukemic cells from normal hematopoietic cells, thereby providing diagnostic and prognostic utility.

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN):

• BPDCN, a rare and aggressive hematologic malignancy, is characterized by high levels of IL3RA expression. IL3RA-targeted therapies, particularly tagraxofusp, have gained FDA approval for treating BPDCN, where it selectively targets and kills CD123-positive cells.
• Due to its specificity for BPDCN cells, IL3RA serves as both a therapeutic target and a diagnostic marker for this disease.

Autoimmune and Inflammatory Diseases:

• Given its role in immune cell proliferation and activation, dysregulated IL3RA signaling may contribute to inflammatory diseases. Elevated IL-3 and IL3RA expression have been observed in inflammatory and autoimmune conditions, although further research is necessary to fully elucidate IL3RA’s involvement.
• Targeting IL3RA or modulating IL-3 levels in conditions characterized by excessive immune activation could provide novel therapeutic approaches in autoimmune and allergic diseases.

Allergic Disorders:

• IL3RA expression on eosinophils and basophils implicates it in allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. IL3RA signaling enhances survival and activation of these cells in response to allergens, amplifying inflammatory responses.
• Blocking IL3RA or IL-3 signaling could help reduce symptoms in allergic diseases, and ongoing research is exploring IL3RA as a potential therapeutic target in severe allergic conditions.

Summary

IL3RA, the interleukin-3 receptor alpha subunit, is essential in hematopoiesis, immune regulation, and inflammatory responses. As part of the IL-3 receptor complex, IL3RA binds IL-3 and pairs with the CSF2RB subunit to initiate signaling pathways that promote cell proliferation, differentiation, and survival, particularly in myeloid and progenitor cells. Structurally, IL3RA consists of an extracellular domain with cytokine-binding regions, a transmembrane segment, and a short intracellular region that relies on the beta subunit for signal transduction.

Clinically, IL3RA is significant in hematologic malignancies such as AML and BPDCN, where it is overexpressed and contributes to disease progression. IL3RA-targeted therapies, like tagraxofusp, have shown efficacy in treating BPDCN and AML, making it a promising therapeutic target. Additionally, IL3RA’s role in allergic and inflammatory diseases provides further potential for therapeutic applications. As research into IL3RA advances, its targeting holds promise for treating diverse conditions related to immune dysregulation and hematologic malignancies.