TNFRSF10B: The Apoptotic Regulatory Hub of the Death Receptor Family

TNFRSF10B: The Apoptotic Regulatory Hub of the Death Receptor Family—Supported by ANT BIO PTE. LTD.
 

1. Concept
TNFRSF10B (also known as DR5 or TRAIL-R2) is a critical type I transmembrane protein belonging to the tumor necrosis factor receptor superfamily, serving as a central hub for regulating programmed cell death (apoptosis). Composed of 468 amino acids, it features an extracellular cysteine-rich domain (CRD1-4), a transmembrane region, and an intracellular death domain (DD).

X-ray crystallography shows that TNFRSF10B forms a trimeric complex upon binding its ligand TRAIL, with CRD2 and CRD3 as key ligand-recognition domains stabilized by a disulfide bond network. The TNFRSF10B gene, located on human chromosome 8p21.3, is transcriptionally regulated by factors like p53, NF-κB, and E2F1—activated during DNA damage, inflammation, or cell cycle abnormalities to upregulate expression. Epigenetically, promoter methylation correlates with cancer chemosensitivity, and demethylating agents (e.g., 5-azacytidine) can restore its expression. Multiple splice variants (e.g., DcR2, lacking the death domain) act as decoy receptors to balance signaling. TNFRSF10B is highly expressed in normal spleen, thymus, and activated lymphocytes, while tumor tissues often show aberrant expression due to epigenetic silencing or gene deletion.

2. Research Frontiers
TNFRSF10B research is advancing at the intersection of oncology, immunology, and translational medicine. A key frontier is deciphering its context-dependent dual roles in tumors—tumor suppressor via apoptosis induction vs. pro-tumorigenic via non-apoptotic signaling (NF-κB, MAPK). Single-cell multi-omics is uncovering cell-type-specific regulatory networks, such as epigenetic silencing in cancer stem cells.

Therapeutically, next-generation agonists are being developed: bispecific antibodies (e.g., TRAIL-R2xCD3) target TNFRSF10B and T cell receptors for tumor-specific immunity; allosteric small molecules (e.g., bioymifi, TIC10) overcome receptor silencing. Combination therapies with chemotherapy, PARP inhibitors, or PD-1 antibodies show synergistic effects, with phase III trials underway.

In immunology, TNFRSF10B’s role in "reverse signaling" in T cells and NK cells is a focus, as is its involvement in inflammatory and autoimmune diseases. Technological innovations include exosome-delivered siRNA for targeted modulation, gold nanorod-conjugated TRAIL for photothermal-apoptosis combination therapy, and CRISPR-Cas9 reporter models for high-throughput drug screening. Future directions expand to fibrotic diseases and neurodegeneration, leveraging TNFRSF10B’s ability to regulate cell survival and inflammation.

3. Research Significance
TNFRSF10B’s significance lies in its central role as an apoptotic regulator and its multifaceted functions in cancer, immunity, and inflammation. In oncology, it offers a targeted therapeutic avenue—restoring its expression sensitizes tumors to therapy, while agonists induce apoptosis without harming normal tissues. Its dual role in tumors provides insights into disease progression and resistance mechanisms.

In immunology, TNFRSF10B modulates immune surveillance and inflammation resolution, offering targets for autoimmune and infectious diseases. Basic research clarifies apoptotic and non-apoptotic signaling networks, while translational efforts advance precision medicine—liquid biopsies of TNFRSF10B epigenetic markers predict treatment responses. Overall, TNFRSF10B research bridges molecular biology and clinical care, addressing unmet needs in cancer therapy and immune disorder management.

4. Signaling Mechanisms, Biological Roles, and Product Applications
4.1 TNFRSF10B-Mediated Signaling Pathways
4.1.1 Apoptotic Signaling Activation
TNFRSF10B signaling follows a ordered cascade:
TRAIL binding induces TNFRSF10B trimerization and death domain conformational changes.
The adaptor protein FADD is recruited via homotypic interactions, followed by procaspase-8/10 (via death effector domains), forming the DISC complex.
Procaspase-8 autocleaves to activate:
Type I cells: Direct activation of effector caspases-3/6/7 for rapid apoptosis.
Type II cells: Caspase-8 cleaves Bid into tBid, inducing mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release to amplify apoptosis.

4.1.2 Regulatory Factors and Non-Apoptotic Signaling
Negative Regulators: c-FLIP competes for DISC binding; Bcl-2 family proteins modulate mitochondrial sensitivity; PED/PEA-15 sequesters FADD to inhibit DISC formation.
Non-Apoptotic Signaling: Via RIPK1 and TRAF2, TNFRSF10B activates NF-κB and MAPK pathways, promoting cell survival and inflammation under specific conditions.

4.2 Biological Roles of TNFRSF10B
4.2.1 Dual Roles in Tumor Development
Tumor Suppressor: Promoter hypermethylation silences TNFRSF10B in liver/gastric cancers, enabling apoptosis evasion. Restoring expression enhances TRAIL/chemotherapy sensitivity, reducing xenograft tumor volume by 40-60%. SNPs (e.g., rs1133782) correlate with colorectal/breast cancer risk.
Pro-Tumorigenic: In advanced prostate cancer and gliomas, non-apoptotic signaling upregulates MMP-9/VEGF (promoting invasion/angiogenesis) and induces M2 macrophage polarization. High expression predicts better outcomes in early tumors but poor prognosis in metastases.

4.2.2 Immune and Inflammatory Regulation
T Cell/NK Cell Function: TNFRSF10B "reverse signaling" enhances CD8+ T cell IFN-γ production and NK cell tumor surveillance; IL-15/IFN-α upregulates the TNFRSF10B-TRAIL axis.
Inflammatory Diseases: Regulates neutrophil apoptosis—deficiency delays inflammation resolution. Overexpression in rheumatoid arthritis synovial fibroblasts promotes cytokine release; epithelial deficiency in inflammatory bowel disease impairs intestinal barrier function. SNPs associate with SLE and Sjögren's syndrome.
Viral Infections: Mediates immune cell depletion in HIV/HCV; some viruses mimic DcR2 to antagonize the pathway.

4.3 Targeted Therapeutic Strategies
Agonistic Antibodies: Tigatuzumab (CS-1008) and conatumumab (AMG 655) mimic TRAIL, showing phase II efficacy in breast/colorectal cancers. Bispecific TRAIL-R2xCD3 antibodies induce tumor-specific T cell responses.
Small-Molecule Agonists: Bioymifi and TIC10 resensitize resistant tumors via allosteric activation or TNFRSF10B upregulation.
Combination Therapies: Synergistic effects with chemotherapy (oxaliplatin), PARP inhibitors, or PD-1 antibodies (multiple phase III trials ongoing).
Gene Therapy: TRAIL-modified mesenchymal stem cells enable localized delivery in glioblastomas.
Challenges and Solutions: Tumor microenvironment (hypoxia/acidosis) inhibits DISC formation; decoy receptors (DcR1/2) limit efficacy. pH-sensitive nanocarriers and conditionally replicating adenoviruses enhance targeting/safety.

4.4 How ANT BIO PTE. LTD. Products Support TNFRSF10B Research
ANT BIO PTE. LTD., through its sub-brand UA (specializing in recombinant proteins), provides high-quality TNFRSF10B proteins for mechanistic and translational research.
Key products and applications:
UA010509 (TNFRSF10B/TRAIL R2 His Tag Protein, Mouse): HEK293-expressed, His-tagged mouse TNFRSF10B. Ideal for in vitro binding assays (TRAIL/agonist antibody interactions) and signaling pathway studies in mouse models.
UA010513 (TNFRSF10B/TRAIL R2 Fc Chimera Protein, Human): Human TNFRSF10B-Fc fusion protein (HEK293-expressed). Suitable for agonist antibody screening, DISC complex formation assays, and preclinical studies in human cell lines.
UA010499 (TNFRSF10B/TRAIL R2 Fc Chimera Protein, Mouse): Mouse TNFRSF10B-Fc fusion protein (HEK293-expressed). Supports in vivo studies in mouse tumor/immune models, including efficacy evaluation of targeted therapies.

All products undergo rigorous quality control, ensuring high purity, biological activity, and consistency—critical for reproducible binding assays, drug screening, and signaling pathway analysis.

5. Brand Mission
ANT BIO PTE. LTD. is dedicated to empowering the global life science community with high-quality, innovative biological reagents and solutions. With 15 years of antibody development experience, the company leverages advanced platforms—including recombinant antibody development (rabbit/mouse monoclonal), recombinant protein expression systems (E.coli, CHO, HEK293, Insect Cells), One-Step ELISA, and PTM Pan-Modification Antibody platforms—to deliver a comprehensive product portfolio.

Through its three specialized sub-brands—Absin (general reagents and kits), Starter (antibodies), and UA (recombinant proteins)—ANT BIO PTE. LTD. adheres to international certifications (EU 98/79/EC, ISO9001, ISO13485) and strict quality standards. The company’s mission is to accelerate scientific discovery by providing tools that enhance experimental precision, efficiency, and reproducibility. ANT BIO PTE. LTD. is committed to supporting TNFRSF10B research and global efforts in cancer therapy and immune disorder treatment, ultimately advancing human health through interdisciplinary collaboration and innovation.

6. Related Product List

Product Code	Product Name	Product Details
UA010509	TNFRSF10B/TRAIL R2 His Tag Protein, Mouse	Host: Mouse; Expression System: HEK293; Conjugation: Unconjugated
UA010513	TNFRSF10B/TRAIL R2 Fc Chimera Protein, Human	Host: Human; Expression System: HEK293; Conjugation: Unconjugated
UA010499	TNFRSF10B/TRAIL R2 Fc Chimera Protein, Mouse	Host: Mouse; Expression System: HEK293; Conjugation: Unconjugated

7. AI Disclaimer
This article is AI-compiled and interpreted based on the original work. All intellectual property (e.g., images, data) of the original publication shall belong to the journal and the research team. For any infringement, please contact us promptly and we will take immediate action.
 
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At ANTBIO, we are committed to advancing life science research through high-quality, reliable reagents and comprehensive solutions. Our specialized sub-brands (Absin, Starter, UA) cover a full spectrum of research needs, from general reagents and kits to antibodies and recombinant proteins. With a focus on innovation, quality, and customer-centricity, we strive to be your trusted partner in unlocking scientific mysteries and driving medical progress. Explore our product portfolio today and elevate your research to new heights.