CLEC7A - C-type lectin domain containing 7A |Elisa - Clia - Antibody - Protein

Background

CLEC7A, also known as C-type lectin domain-containing protein 7A or Dectin-1, is a receptor mainly expressed on myeloid cells, especially dendritic cells, macrophages, neutrophils, and subsets of monocytes. As part of the C-type lectin receptor (CLR) family, CLEC7A is essential for recognizing pathogenic fungi, bacteria, and other microbial structures, making it a crucial component of the innate immune system. CLEC7A identifies β-glucans, polysaccharides found abundantly in fungal cell walls, and this interaction triggers immune responses, including phagocytosis and cytokine production. In addition to microbial defense, CLEC7A has roles in modulating sterile inflammatory responses, which link it to several inflammatory and autoimmune diseases.

CLEC7A is predominantly studied for its role in antifungal immunity, particularly in recognizing β-1,3-glucan, a prominent component of fungal cell walls, leading to immune activation that aids in pathogen elimination. Because CLEC7A mediates signaling independently of other pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), it provides a unique and essential pathway in immunity. Its function also encompasses regulating immune responses to ensure that inflammation does not persist unnecessarily, as this can lead to tissue damage and chronic inflammatory states.

Protein Structure

The structure of CLEC7A is integral to its function in immune recognition and signaling:

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

• The extracellular CTLD of CLEC7A is responsible for binding β-glucans on fungal and bacterial cell walls. Unlike other C-type lectins, CLEC7A can bind its ligands independently of calcium ions, a feature that enhances its ability to recognize a diverse range of microbial carbohydrates. The β-glucan-binding activity of CLEC7A is highly specific, which allows the immune system to detect fungi and bacteria based on cell wall composition.
• The CTLD has a carbohydrate-recognition domain (CRD) that binds β-glucans in a conformation-dependent manner, enabling selective recognition and binding affinity for different types of β-glucan polysaccharides.

Stalk and Neck Region:

• CLEC7A contains a stalk region between the CTLD and transmembrane region. This structure provides flexibility, allowing the CTLD to interact with ligands optimally and improving receptor accessibility to pathogen cell walls.
• The neck region contributes to the formation of receptor dimers. CLEC7A functions as a homodimer, which is necessary for high-affinity ligand binding and efficient downstream signaling.

Transmembrane Domain:

• CLEC7A has a single transmembrane helix that anchors it to the cell membrane. This domain ensures the structural stability of the receptor and positions the extracellular CTLD for optimal interaction with microbial cell walls.

Cytoplasmic Tail:

• CLEC7A’s cytoplasmic tail contains an immunoreceptor tyrosine-based activation-like motif (ITAM-like motif), essential for initiating signaling cascades following ligand binding. This motif is phosphorylated upon receptor-ligand interaction, leading to recruitment of spleen tyrosine kinase (Syk) and downstream activation of NF-κB and MAPK signaling pathways.
• These signaling pathways induce a pro-inflammatory response, cytokine production, and phagocytosis, which are crucial for pathogen clearance. This ITAM-like signaling distinguishes CLEC7A from other CLRs that do not independently initiate signaling upon ligand binding.

Classification and Subtypes

CLEC7A is classified under the C-type lectin receptor family, specifically within the group of dectin-like receptors, which are involved in immune recognition and host defense. It is closely related to other CLRs such as CLEC6A (Dectin-2) and CLEC4E (Mincle), which also play roles in recognizing microbial components. Unlike some other CLRs, CLEC7A does not have major subtypes or isoforms, as its primary function and ligand specificity are highly conserved. However, differences in CLEC7A expression across immune cell types provide functional diversity within immune responses.

Function and Biological Significance

The role of CLEC7A in immunity extends across several key functions:

Pathogen Recognition and Immune Activation:

• CLEC7A’s primary role is in recognizing β-glucan structures in the cell walls of fungi such as Candida albicans, Aspergillus fumigatus, and Pneumocystis jirovecii. This recognition is vital for triggering phagocytosis and the production of inflammatory cytokines that recruit and activate additional immune cells.
• Upon binding to β-glucan, CLEC7A activates Syk-dependent signaling pathways, leading to the activation of transcription factors like NF-κB, which in turn induce cytokine production. Key cytokines produced include IL-6, TNF-α, and IL-23, which promote inflammation and enhance the antifungal response.

Phagocytosis and Reactive Oxygen Species (ROS) Production:

• CLEC7A engagement promotes phagocytosis, a process where immune cells engulf and destroy pathogens. Additionally, it induces the production of reactive oxygen species (ROS), which have antimicrobial properties, further enhancing pathogen elimination.
• This receptor-mediated phagocytosis helps clear fungal pathogens efficiently, reducing the likelihood of systemic fungal infections in immunocompetent individuals.

T-helper Cell Polarization:

• CLEC7A plays a role in modulating adaptive immunity, specifically influencing the differentiation of T-helper cells. By promoting the release of IL-23 and other cytokines, CLEC7A supports Th17 cell responses, which are essential for controlling fungal infections.
• The Th17 response, characterized by the production of IL-17, aids in recruiting neutrophils to infection sites and enhancing mucosal immunity, thus providing a layer of defense against fungal pathogens.

Regulation of Sterile Inflammation:

• CLEC7A also responds to sterile inflammatory signals, where it can recognize endogenous ligands such as damaged tissue components. This capability allows CLEC7A to contribute to inflammation in non-infectious contexts, such as tissue injury or autoimmunity.
• Its activity in sterile inflammation implicates it in processes beyond microbial defense, as it can contribute to immune regulation, wound healing, and the resolution of inflammation.

Clinical Issues

Fungal Infections:

• Deficiencies or mutations in CLEC7A have been linked to increased susceptibility to fungal infections, especially systemic infections with Candida and other fungi. Patients with impaired CLEC7A function may exhibit inadequate immune responses to fungal pathogens, resulting in severe infections.
• Conversely, overactivation of CLEC7A can lead to excessive inflammation, which may contribute to symptoms in chronic fungal infections or inflammatory conditions associated with fungal colonization.

Autoimmune and Inflammatory Diseases:

• CLEC7A has been implicated in several autoimmune and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease, due to its role in amplifying inflammatory responses. Inappropriate activation of CLEC7A in the absence of infection can lead to chronic inflammation and tissue damage.
• Targeting CLEC7A or its signaling pathways has been explored as a potential therapeutic approach in these conditions, aiming to reduce excessive immune activation without compromising antimicrobial defense.

Cancer:

• There is growing evidence that CLEC7A may play a role in tumor immunity. By influencing macrophage and dendritic cell function, CLEC7A could impact the immune response within the tumor microenvironment, potentially enhancing or suppressing antitumor immunity.
• Some studies suggest that CLEC7A expression on tumor-associated macrophages may promote a pro-inflammatory environment, which could inhibit tumor progression. However, further research is needed to clarify its exact role in cancer and whether CLEC7A-targeted therapies could benefit cancer treatment.

Therapeutic Targeting:

• CLEC7A has attracted interest as a therapeutic target due to its central role in fungal infections and inflammation. CLEC7A agonists could potentially enhance immune responses in immunocompromised individuals at high risk of fungal infections, while antagonists might help mitigate inflammation in autoimmune or chronic inflammatory conditions.
• Additionally, modulating CLEC7A could have implications for improving immune responses in other contexts, such as vaccine adjuvant development, where enhancing immune activation is beneficial.

Summary

CLEC7A, or Dectin-1, is a crucial receptor in the innate immune system that detects fungal and bacterial pathogens through its C-type lectin-like domain, which binds to β-glucan. This receptor’s unique structure includes an extracellular CTLD for ligand recognition, a transmembrane region for membrane anchoring, and a cytoplasmic tail with an ITAM-like motif essential for initiating intracellular signaling. CLEC7A activation results in the production of pro-inflammatory cytokines, phagocytosis, and ROS generation, all of which are critical for pathogen clearance.

The biological significance of CLEC7A is highlighted in antifungal immunity, where it triggers immune responses against fungal pathogens, supports Th17 cell responses, and participates in sterile inflammation. Clinically, CLEC7A’s function is associated with susceptibility to fungal infections, and its dysregulation is linked to autoimmune and inflammatory diseases. CLEC7A’s role in immune regulation and pathogen recognition makes it a promising therapeutic target for enhancing immune responses in fungal infections and modulating inflammation in autoimmune conditions.