CLEC4C

Official Full Name

C-type lectin domain family 4 member C

Organism

Homo sapiens

GeneID

170482

Background

This gene encodes a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. Members of this family share a common protein fold and have diverse functions, such as cell adhesion, cell-cell signalling, glycoprotein turnover, and roles in inflammation and immune response. The encoded type 2 transmembrane protein may play a role in dendritic cell function. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

Synonyms

DLEC; HECL; BDCA2; CD303; BDCA-2; CLECSF7; CLECSF11; PRO34150;

Protein Sequence

MVPEEEPQDREKGLWWFQLKVWSMAVVSILLLSVCFTVSSVVPHNFMYSKTVKRLSKLREYQQYHPSLTCVMEGKDIEDWSCCPTPWTSFQSSCYFISTGMQSWTKSQKNCSVMGADLVVINTREEQDFIIQNLKRNSSYFLGLSDPGGRRHWQWVDQTPYNENVTFWHSGEPNNLDERCAIINFRSSEEWGWNDIHCHVPQKSICKMKKIYI

Open

Disease

Cutaneous lupus erythematosus, Lupus erythematosus

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The CLEC4C gene, located on chromosome 12 in humans, encodes a type II C-type lectin receptor extensively expressed on the surface of plasmacytoid dendritic cells (pDCs). pDCs are a subset of dendritic cells with unique immune functions and play a vital role in antiviral and immune regulation through the abundant secretion of type I interferons (IFN-I). The glycoprotein encoded by the CLEC4C gene, BDCA2, forms a specialized receptor on dendritic cells that partakes in glycan recognition, especially binding to various sugar moieties like galactose-terminal residues.

The BDCA2 receptor uses its extracellular carbohydrate recognition domain (CRD) to bind molecules like mannose, glucose, or N-acetylglucosamine, which further involves pathogen recognition and immune response regulation. The intracellular portion interacts with the FcεRIγ chain, triggering intracellular signaling pathways that activate tyrosine kinases and phospholipase C, thereby regulating cell function. BDCA2 activation is closely linked to interferon secretion and can, under certain conditions, suppress immune responses by reducing IFN-I expression, playing a dual role in immune regulation.

Figure 1 illustrates CD303/BDCA-2 signaling on plasmacytoid dendritic cells, showing how it binds to specific glycans on IgG, associates with the FcεRI c-chain, and initiates a cascade leading to calcium influx, NF-jB inhibition, and type I interferon expression. Figure 1. CD303/BDCA-2 signaling on plasmacytoid dendritic cell. (Wilson NR, et al., 2022)

Role of BDCA2 in Immune Response

BDCA2 has a complex role in the immune system, particularly in the function of dendritic cells. These cells are crucial antigen-presenting cells that effectively recognize pathogens and activate T cells, initiating specific immune responses. BDCA2 helps recognize and capture specific glycans, promoting pathogen endocytosis, and subsequently, through antigen processing and peptide loading, presents them to T cells, thereby activating specific immune responses.

Notably, BDCA2's function is not limited to promoting immune responses; it also plays a role in modulating immune tolerance and suppressing immune reactions. Activation of the BDCA2 receptor can modulate excessive immune responses by inhibiting NF-kB activation and reducing interferon production. For instance, in autoimmune diseases like systemic lupus erythematosus (SLE), pDCs can reduce excessive IFN-I production via BDCA2, thus inhibiting abnormal immune responses and alleviating disease symptoms.

Relationship Between BDCA2 and Diseases

The CLEC4C gene is closely related to the onset and development of various diseases, particularly autoimmune diseases, viral infections, and tumor immune evasion. First, BDCA2 plays a significant role in the pathogenesis of systemic lupus erythematosus (SLE). Dendritic cells in SLE patients often display dysfunction, secreting excessive IFN-I, a process closely related to BDCA2 expression. As such, BDCA2 is considered a potential target for blocking SLE pathogenesis, potentially serving as a new strategy in SLE treatment by regulating immune responses and reducing excessive IFN-I production.

Furthermore, BDCA2 has significant immune functions in viral infections. BDCA2 receptors can recognize pathogens like hepatitis C virus (HCV), HIV, and influenza virus, promoting interferon secretion by activating pDCs, thereby inhibiting viral replication and spread. Notably, in certain infectious diseases such as influenza and COVID-19, BDCA2 receptor activation can enhance immune system recognition and clearance of viruses, offering protective effects.

BDCA2 expression is also significant in tumor immune evasion. Some tumor cells evade immune surveillance by altering dendritic cell functions, particularly by inhibiting pDC maturation and function. The role of the BDCA2 receptor encoded by the CLEC4C gene in the tumor immune microenvironment is not yet fully understood. However, existing research indicates that increased pDCs in certain cancer types are closely related to tumor immune evasion mechanisms. Thus, targeting the BDCA2 receptor might become a new approach in tumor immunotherapy.

The potential of BDCA2 as an Immunotherapy Target

BDCA2 is seen as a potential immunotherapy target as it plays two different functions in the immune system. In many immunological-related disorders, adjusting BDCA2 activity might result in immune tolerance or boost. In autoimmune disorders, for instance, BDCA2's inhibitory activity could assist in reducing strong immune responses; in infectious diseases, on the other hand, improving BDCA2 function might support antiviral immune responses.

Recently, researchers have attempted to modulate BDCA2 function through monoclonal antibodies, vaccines, or small molecule inhibitors for therapeutic purposes. For example, monoclonal antibodies targeting BDCA2 have been shown to inhibit IFN-I production by pDCs and effectively regulate immune tolerance, offering new insights into autoimmune disease treatment. Simultaneously, BDCA2 activation is regarded as a potential way to enhance the body's immune response to viral infections by enhancing pDC function.

References:

Wilson NR, Bover L, et al. CD303 (BDCA-2) - a potential novel target for therapy in hematologic malignancies. Leuk Lymphoma. 2022 Jan;63(1):19-30.
Chen X, Li S, Jiang ZM, et al. C-type Lectin Domain Family 4 Member G (CLEC4G) Is a Negative Marker for CD34 in the Evolution of Liver Pathogenesis. Ann Clin Lab Sci. 2023 Jul;53(4):516-528.

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