TNFRSF10C - TNF receptor superfamily member 10C | Elisa - Clia - Antibody - Protein

Background

TNFRSF10C (TNF receptor superfamily member 10C), also known as TRAIL-R3 or Decoy Receptor 1 (DcR1), is part of the TNF receptor superfamily and specifically the death receptor subset involved in binding the ligand TRAIL (TNF-related apoptosis-inducing ligand). Unlike other TRAIL receptors, such as TNFRSF10A (TRAIL-R1) and TNFRSF10B (TRAIL-R2), which can initiate apoptosis upon TRAIL binding, TNFRSF10C is categorized as a “decoy” receptor. This classification is due to its structural attributes that prevent it from transmitting apoptotic signals. Instead, TNFRSF10C functions by binding TRAIL and preventing it from interacting with apoptosis-inducing receptors, thereby modulating apoptosis sensitivity in cells.

TNFRSF10C is predominantly expressed in normal, non-transformed tissues, suggesting a role in protecting healthy cells from TRAIL-induced apoptosis. It has gained scientific interest due to its potential implications in cancer biology, where it may contribute to tumor resistance against TRAIL-based therapies.

Protein Structure

TNFRSF10C has a unique protein structure among TRAIL receptors. It is classified as a type I transmembrane protein and has the following notable structural features:

Extracellular Domain (ECD):

• The extracellular domain of TNFRSF10C contains three cysteine-rich domains (CRDs), which are characteristic of TNF receptor family proteins. These CRDs are critical for ligand (TRAIL) binding, allowing TNFRSF10C to compete with apoptosis-inducing TRAIL receptors (TRAIL-R1 and TRAIL-R2) for TRAIL binding.
• Unlike TRAIL-R1 and TRAIL-R2, TNFRSF10C has a higher affinity for TRAIL but does not trigger apoptosis upon ligand binding, as it lacks the necessary intracellular signaling components.

Transmembrane Domain (TMD):

• The transmembrane domain anchors TNFRSF10C within the cell membrane, allowing it to serve as a receptor for extracellular TRAIL. This region is essential for membrane stability and ensures that TNFRSF10C is positioned to interact effectively with circulating TRAIL.

Lack of Death Domain (DD):

• A defining characteristic of TNFRSF10C is its absence of a death domain within its intracellular tail. This domain is critical for apoptotic signaling in death receptors like TRAIL-R1 and TRAIL-R2, as it enables recruitment of adaptor proteins such as FADD (Fas-associated death domain) to initiate the apoptotic cascade.
• Without the death domain, TNFRSF10C cannot recruit these signaling molecules or form the death-inducing signaling complex (DISC). Consequently, TNFRSF10C functions solely as a binding receptor and does not transmit any apoptotic signals.

This structural design positions TNFRSF10C as a decoy receptor, serving to limit the bioavailability of TRAIL for apoptosis-inducing receptors.

Classification and Subtypes

TNFRSF10C belongs to the TNF receptor superfamily, specifically classified among TRAIL receptors. Within this subgroup, TRAIL receptors are divided based on their ability to initiate apoptosis. TNFRSF10A and TNFRSF10B contain death domains, making them functional apoptotic receptors. In contrast, TNFRSF10C and TNFRSF10D (TRAIL-R4) lack functional death domains and therefore do not induce apoptosis, classifying them as decoy receptors.

Decoy receptors such as TNFRSF10C modulate TRAIL sensitivity and help prevent unintended cell death, providing a balance within the TRAIL signaling system. No known subtypes of TNFRSF10C exist, as it operates as a single, distinct entity within the TNF receptor family.

Function and Biological Significance

Regulation of Apoptosis:

• The primary function of TNFRSF10C is to regulate apoptosis by acting as a decoy for TRAIL. By binding TRAIL with high affinity, TNFRSF10C reduces the availability of TRAIL for TRAIL-R1 and TRAIL-R2, effectively modulating apoptosis signaling in cells.
• This regulation is particularly relevant in normal, non-transformed cells, where TNFRSF10C expression is typically higher. By limiting TRAIL-induced apoptosis, TNFRSF10C protects healthy tissues from excessive cell death, maintaining tissue integrity and function.

Cell Survival and Immune Modulation:

• TNFRSF10C may contribute to cell survival in certain contexts by shielding cells from TRAIL-mediated apoptosis. This protective function is critical for immune regulation, as TRAIL is involved in targeting and removing infected, damaged, or malignant cells.
• TNFRSF10C’s presence in normal cells serves as a checkpoint, allowing immune cells to selectively target TRAIL-sensitive cells, while protecting non-transformed cells from accidental apoptosis.

Tumor Biology:

• In the context of cancer, TNFRSF10C may play a dual role. On the one hand, its expression in healthy tissues is beneficial for protecting normal cells from unintended apoptosis. On the other hand, certain cancer cells may exploit TNFRSF10C expression to evade TRAIL-induced apoptosis.
• Upregulation of TNFRSF10C has been observed in some cancers, contributing to tumor resistance against immune-mediated apoptosis and TRAIL-based therapies. Therefore, TNFRSF10C’s role in cancer biology has significant implications for developing therapeutic strategies targeting TRAIL receptors.

Clinical Issues

Cancer Therapeutics:

• Given its role as a decoy receptor, TNFRSF10C presents challenges in cancer therapy that involves TRAIL. Cancer cells with elevated levels of TNFRSF10C are more resistant to TRAIL-induced apoptosis, which can reduce the effectiveness of TRAIL-based therapies.
• Therapeutic approaches to overcome this resistance include developing agents that selectively target TRAIL-R1 and TRAIL-R2 or downregulate TNFRSF10C expression in tumors, enhancing TRAIL sensitivity. Research on monoclonal antibodies and TRAIL receptor-specific agonists aims to improve the efficacy of TRAIL-targeted cancer treatments.

Autoimmune and Inflammatory Disorders:

• TNFRSF10C expression in normal tissues also plays a role in regulating apoptosis in autoimmune and inflammatory diseases. By preventing unnecessary cell death, TNFRSF10C contributes to immune homeostasis and helps modulate inflammation.
• However, dysregulated TNFRSF10C expression may contribute to autoimmune pathologies by affecting the removal of immune cells, thereby altering immune tolerance. Exploring TNFRSF10C as a therapeutic target in these diseases is an emerging area of research, with a focus on modulating TRAIL pathways to control inflammation.

Resistance in Viral Infections:

• Some viruses have been shown to upregulate TNFRSF10C in infected cells, which can help the virus evade the host immune response by preventing TRAIL-induced apoptosis of infected cells. Targeting TNFRSF10C may offer a potential strategy to enhance immune clearance of virus-infected cells.

Summary

TNFRSF10C, or TRAIL-R3, is a member of the TNF receptor superfamily and acts as a decoy receptor for TRAIL. Unlike other TRAIL receptors with apoptotic functions, TNFRSF10C lacks an intracellular death domain and cannot initiate apoptosis. Instead, it modulates TRAIL bioavailability, protecting normal cells from unwanted apoptosis. This decoy mechanism is significant for immune surveillance and homeostasis, ensuring that TRAIL-induced apoptosis is primarily directed at abnormal or malignant cells while sparing healthy tissue.

In cancer, TNFRSF10C expression can contribute to tumor resistance against TRAIL-based therapies, posing challenges for therapeutic strategies targeting TRAIL receptors. The presence of TNFRSF10C in normal tissues supports its role in immune regulation and in controlling inflammation, although its dysregulation may influence autoimmune diseases and viral persistence. Given its dual role in apoptosis modulation and immune protection, TNFRSF10C remains a significant focus in understanding and manipulating TRAIL signaling pathways for therapeutic benefit.