CLEC3B

C-type lectin domain family 3 member B (CLEC3B), also known as tetranectin, is a soluble C-type lectin involved in extracellular matrix remodeling, fibrinolysis and immune modulation. Given its role in cancer progression, tissue remodeling and immune regulation, CLEC3B has emerged as a potential drug target.

NCBI Gene ID: 7123

UniProtKB ID: P05452

Structure and Molecular Characteristics of CLEC3B

CLEC3B is a 20-25 kDa glycoprotein secreted primarily by hepatocytes and various connective tissue cells. Structurally, it contains a single C-type lectin-like domain (CTLD) that binds to plasminogen and promotes its activation to plasmin, a key enzyme in fibrinolysis. Unlike classical C-type lectins, CLEC3B does not primarily function in carbohydrate recognition, but rather interacts with protein ligands such as plasminogen and fibrinogen.

Figure 1. Structure of the CLEC3B protein, PDB code: 1HTN.

Biological Functions of CLEC3B

• Fibrinolysis and tissue remodeling: CLEC3B enhances plasminogen activation, thereby contributing to extracellular matrix degradation and wound healing. Its role in tissue remodeling makes it essential for physiological processes like angiogenesis and tissue repair.
• Cancer progression: Studies suggest that CLEC3B expression is altered in various malignancies. While high levels may correlate with tumor suppression in some cancers, downregulation of CLEC3B has been associated with poor prognosis in hepatocellular carcinoma and lung cancer.
• Immune modulation: CLEC3B interacts with immune components to influence inflammatory responses and immune cell recruitment. It has been suggested to modulate macrophage activity, which may have implications in inflammatory and autoimmune diseases.
• Bone metabolism: CLEC3B has been implicated in bone homeostasis, with potential roles in osteoclast differentiation and mineralization.

CLEC3B as a Drug Target

• Cancer therapy: CLEC3B expression levels correlate with tumor progression and metastasis. Targeting CLEC3B activity with monoclonal antibodies or small molecule inhibitors could alter the tumor microenvironment and reduce cancer cell invasion and metastasis.
• Thrombotic and cardiovascular diseases: CLEC3B facilitates plasminogen activation, which affects fibrinolysis. Drugs targeting CLEC3B interactions may help in the development of anticoagulant therapies to prevent thrombosis or excessive clot formation.
• Fibrosis and tissue repair: Dysregulated CLEC3B contributes to fibrotic diseases. Modulation of CLEC3B function by recombinant proteins may support controlled tissue repair and wound healing, preventing excessive scarring and fibrosis.
• Autoimmune and inflammatory disorders: CLEC3B's role in immune modulation makes it a candidate for therapies aimed at controlling inflammatory responses. Therapeutic approaches include peptide-based drugs and immunomodulators that regulate CLEC3B activity.

New Insights about CLEC3B

Case 1: CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment

Lung cancer remains the leading cause of cancer-related deaths worldwide, highlighting the urgent need for reliable biomarkers for early diagnosis and prognosis. CLEC3B has been implicated in several cancers, but its role in lung cancer remains unclear.

To investigate the significance of CLEC3B, the researchers analyzed data from the GEO, TCGA and Oncomine databases and validated the results using real-time PCR (15 patient samples) and immunohistochemistry (34 patient samples). The study found that CLEC3B is significantly downregulated in lung cancer, especially in early stage (IA) patients (p < 0.001). It demonstrated high diagnostic accuracy and was associated with poor progression-free survival and overall survival. Multivariate analysis further confirmed CLEC3B as an independent risk factor for disease-free survival. In addition, CLEC3B was associated with immune infiltration and activation, particularly in lung squamous cell carcinoma.

These findings suggest that CLEC3B is a potential diagnostic and prognostic biomarker for lung cancer and may serve as an immune-related therapeutic target.

Figure 2. Correlation of CLEC3B expression with immune infiltration level in ADC and SCC. a, b Comparison of CLEC3B expression between the high and low immune score groups of ADC and SCC. c–p CLEC3B is related to tumor purity and immune infiltration levels of ADC and SCC by TIMER analysis. ADC, adenocarcinoma; SCC, squamous cell carcinoma; ns, no significance. ***p < 0.0. (Sun et al., 2020)

Case 2: CLEC3B is a novel causative gene for macular-retinal dystrophy

Macular degeneration is the leading cause of blindness worldwide, and this study aimed to identify a new subtype of macular-retinal dystrophy and its genetic predisposition in five families. The study identified a pathogenic CLEC3B variant in five multigenerational families diagnosed with autosomal dominant maculoretinopathy and implicated tetranectin, a plasminogen kringle-4 binding protein, in disease progression. Mice injected with the CLEC3B variant exhibited subretinal hyperreflective deposits, reduced retinal thickness, and diminished electroretinographic responses, while optokinetic tracking revealed significantly impaired spatial frequency, indicating visual dysfunction. These findings establish a new subtype of macular-retinal dystrophy associated with CLEC3B and provide new insights into the genetic basis of maculoretinopathy.

Figure 3. CLEC3B is a novel causative gene for macular-retinal dystrophy (Zhou et al., 2022)

Related Therapeutic Proteins

Several therapeutic proteins have been explored for targeting CLEC3B or its associated pathways:

• Recombinant plasminogen activators: Given the role of CLEC3B in plasminogen activation, recombinant plasminogen activators (e.g. alteplase, tenecteplase) have been used in thrombolytic therapy, indirectly affecting CLEC3B-mediated fibrinolysis.
• Monoclonal antibodies: Experimental monoclonal antibodies targeting CLEC3B interactions are being investigated for their potential in the treatment of oncology and inflammatory diseases.
• Extracellular matrix modulators: Therapeutic proteins designed to influence ECM remodeling, such as collagen-targeting agents, may work in conjunction with CLEC3B modulation to regulate tissue repair and fibrosis.

Clinical Implications and Future Perspectives

With CLEC3B emerging as a potential biomarker and drug target, ongoing research is focused on developing targeted therapies that exploit its role in fibrinolysis, cancer progression and immune regulation. Advances in monoclonal antibody therapy, recombinant protein engineering, and small molecule inhibitors hold promise for translating CLEC3B-targeted approaches into clinical practice.

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References

1. Sun J, Xie T, Jamal M, et al. CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment. Cancer Cell Int. 2020;20(1):106. doi:10.1186/s12935-020-01183-1
2. Zhou R, Mawatari G, Cai XB, et al. CLEC3B is a novel causative gene for macular-retinal dystrophy. Genetics in Medicine. 2022;24(6):1249-1260. doi:10.1016/j.gim.2022.02.012