CLEC4A - C-type lectin domain family 4 member A |Elisa - Clia - Antibody - Protein

Background

CLEC4A (C-type lectin domain family 4 member A), also known as DCIR (dendritic cell immunoreceptor), is a receptor found on the surface of various immune cells, particularly dendritic cells (DCs) and monocytes. CLEC4A is part of the C-type lectin receptor (CLR) family, a group of proteins that play key roles in the immune system, especially in pathogen recognition, immune homeostasis, and inflammatory responses. As a member of this family, CLEC4A can recognize and bind to carbohydrate structures found on pathogens, self-antigens, and damaged cells. This binding facilitates immune responses and communication between cells of the immune system.

CLEC4A has an important immunomodulatory role and is involved in both activating and inhibitory signaling pathways. Its ability to bind self-antigens and regulate immune responses is critical in maintaining immune tolerance, thus preventing autoimmune responses. Its expression in dendritic cells and other antigen-presenting cells highlights its relevance in adaptive immunity, where it influences T-cell activation and the shaping of immune responses. Additionally, CLEC4A is implicated in various autoimmune diseases and infections, making it an important target for therapeutic research.

Protein Structure

CLEC4A is a transmembrane protein with a C-type lectin domain and follows the structure typical of CLRs:

Extracellular C-type Lectin-like Domain (CTLD):

• The extracellular domain of CLEC4A contains a C-type lectin-like domain (CTLD), which is responsible for carbohydrate recognition. This domain allows CLEC4A to bind glycan structures on pathogens, apoptotic cells, and self-antigens.
• Unlike other C-type lectins that require calcium for carbohydrate binding, CLEC4A does not require calcium, which means it may bind a broader array of ligands and have greater functional flexibility.

Neck Region:

• Between the CTLD and the transmembrane domain, CLEC4A has a short neck region that contributes to the protein’s overall structural orientation and the accessibility of its binding sites. This segment provides flexibility, allowing the extracellular domain to orient appropriately for ligand binding.

Transmembrane Domain:

• CLEC4A has a single transmembrane region, which anchors the protein within the cell membrane, making it accessible to extracellular ligands and participating in signaling pathways.
• The transmembrane domain’s hydrophobic nature stabilizes CLEC4A within the cell membrane, positioning the CTLD outward.

Cytoplasmic Tail with Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM):

• The cytoplasmic region of CLEC4A includes an immunoreceptor tyrosine-based inhibitory motif (ITIM). This ITIM motif is crucial for transmitting inhibitory signals that downregulate immune cell activation.
• Upon binding a ligand, the ITIM motif recruits phosphatases like SHP-1 and SHP-2, which then mediate inhibitory signaling pathways that dampen cellular responses, contributing to immune tolerance and homeostasis.

Classification and Subtypes

CLEC4A is classified under the C-type lectin domain family 4 (CLEC4), specifically within the DCIR (dendritic cell immunoreceptor) subgroup. It does not have well-documented subtypes or isoforms in humans, although there is evidence of differential expression patterns in immune cells that may indicate functional variations in different immune contexts. The CLEC4 family includes other receptors like CLEC4D and CLEC4E, each with unique roles in immune responses, but CLEC4A is unique for its ITIM-containing cytoplasmic tail, making it an inhibitory receptor.

Function and Biological Significance

CLEC4A plays a multifaceted role in immune regulation, with functions that include pathogen recognition, modulation of immune cell signaling, and maintenance of immune tolerance:

Pathogen Recognition:

• Through its C-type lectin domain, CLEC4A binds to carbohydrate structures on pathogens, including fungi, bacteria, and viruses. This recognition enables immune cells, particularly dendritic cells, to initiate appropriate immune responses.
• In binding to pathogens, CLEC4A serves as a pattern recognition receptor (PRR), a role essential in early innate immune responses. This binding triggers immune activation pathways, leading to the secretion of cytokines and chemokines that recruit additional immune cells to the site of infection.

Inhibition of Immune Responses:

• CLEC4A is involved in inhibitory signaling pathways due to its ITIM motif. After ligand binding, the ITIM domain interacts with phosphatases like SHP-1 and SHP-2, leading to a reduction in immune cell activation.
• This inhibitory function is particularly relevant in preventing overactivation of immune responses and maintaining immune homeostasis. It has a role in limiting inflammation, reducing potential damage to host tissues during infections, and regulating immune tolerance.

Role in Adaptive Immunity and Antigen Presentation:

• As a receptor on dendritic cells, CLEC4A influences antigen presentation to T-cells. By binding antigens, CLEC4A can modulate the dendritic cell’s ability to prime T-cells and influence the differentiation of T-helper cell subsets, which are critical in determining the direction of adaptive immune responses.
• Through these interactions, CLEC4A helps shape the immune response, either promoting tolerance to self-antigens or aiding in the generation of effective immunity against pathogens.

Maintenance of Immune Tolerance:

• By recognizing self-antigens, CLEC4A plays a role in promoting immune tolerance, which is essential for preventing autoimmune reactions. It aids in the clearance of apoptotic cells, further contributing to tolerance and preventing the immune system from targeting self-cells.
• Its expression and function are modulated to prevent excessive immune responses, a feature that is critical in autoimmune conditions where self-tolerance is disrupted.

Clinical Issues

Autoimmune Diseases:

• Dysregulation of CLEC4A has been implicated in autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. In these conditions, the inhibitory function of CLEC4A may be compromised, leading to increased activation of immune cells and the breakdown of self-tolerance.
• Genetic variations in the CLEC4A gene are associated with an increased risk of autoimmune conditions, suggesting a genetic basis for CLEC4A’s role in immune regulation. Targeting CLEC4A signaling pathways has been considered as a therapeutic strategy for autoimmune disease management.

Infectious Diseases:

• CLEC4A’s role as a pathogen recognition receptor makes it relevant in infectious diseases. In fungal infections, CLEC4A is involved in the recognition of fungal cell wall components, which initiates immune responses. However, excessive activation of CLEC4A during infections can sometimes lead to an overwhelming immune response that causes tissue damage.
• Certain pathogens may exploit CLEC4A signaling to avoid immune detection, using it to downregulate immune responses and evade clearance.

Cancer:

• CLEC4A’s inhibitory function has implications in cancer immunology. By dampening immune responses, CLEC4A may contribute to immune escape mechanisms used by tumors, allowing them to evade immune detection and destruction.
• Overexpression of CLEC4A on dendritic cells and macrophages in the tumor microenvironment has been observed in some cancers, where it may suppress anti-tumor immunity. Therapeutic strategies to block CLEC4A or modulate its signaling are under investigation as potential cancer immunotherapies.

Chronic Inflammatory Conditions:

• CLEC4A has been linked to chronic inflammatory conditions due to its role in modulating immune cell activation. Dysregulated CLEC4A signaling can lead to persistent inflammation, which is a feature of chronic diseases like atherosclerosis and chronic obstructive pulmonary disease (COPD).
• Targeting CLEC4A to modulate immune responses may help alleviate inflammation and tissue damage in these chronic conditions.

Summary

CLEC4A (DCIR) is a C-type lectin receptor that is essential for immune regulation, with roles in pathogen recognition, immune inhibition, and maintenance of immune tolerance. Structurally, CLEC4A is characterized by an extracellular C-type lectin-like domain for carbohydrate binding, a short neck region, a transmembrane domain, and a cytoplasmic tail with an ITIM motif that mediates inhibitory signaling. CLEC4A recognizes and binds to carbohydrates on pathogens and self-antigens, facilitating immune modulation.

CLEC4A’s functions include immune cell inhibition, antigen presentation, and immune tolerance, with significant roles in infectious disease, autoimmune regulation, and cancer. Clinically, CLEC4A is implicated in autoimmune diseases, chronic inflammation, and immune escape in cancers. As a result, CLEC4A is an important target for therapeutic research, with potential for interventions aimed at modulating immune responses in autoimmune disorders, infections, and cancer. Its ability to mediate both activation and inhibition of immune pathways underscores its versatility and significance in immune system regulation.