TNFRSF10D - TNF receptor superfamily member 10D | Elisa - Clia - Antibody - Protein

Background

TNFRSF10D, also known as TRAIL-R4 or DcR2 (Decoy Receptor 2), is a member of the tumor necrosis factor receptor superfamily, specifically binding TRAIL (TNF-related apoptosis-inducing ligand). Unlike apoptosis-inducing TRAIL receptors, such as TNFRSF10A (TRAIL-R1) and TNFRSF10B (TRAIL-R2), TNFRSF10D functions primarily as a “decoy” receptor. It plays a modulatory role by binding TRAIL and potentially preventing TRAIL-induced apoptosis in non-transformed cells. TNFRSF10D is unique among TRAIL receptors in that, while it possesses an intracellular tail with a truncated death domain, it lacks the full ability to transduce apoptotic signals. This feature gives it a protective function, especially in healthy cells where it modulates apoptosis sensitivity.

TNFRSF10D is expressed in various normal tissues and has been implicated in protecting these tissues from unwanted TRAIL-mediated apoptosis. It is a subject of considerable interest in the field of cancer biology and immune modulation, as its expression pattern and function influence both tumor immunity and potential cancer cell resistance to TRAIL-based therapies.

Protein Structure

The structure of TNFRSF10D distinguishes it from other TRAIL receptors in several significant ways:

Extracellular Domain (ECD):

• TNFRSF10D contains a typical extracellular domain with three cysteine-rich domains (CRDs), which are conserved motifs in the TNF receptor superfamily. These CRDs are essential for the receptor’s binding affinity to TRAIL, allowing TNFRSF10D to interact with TRAIL in a manner similar to other TRAIL receptors.
• Despite this structural similarity in the extracellular domain, the primary function of TNFRSF10D differs from that of death-inducing receptors. By binding to TRAIL, TNFRSF10D can act as a competitive inhibitor, reducing TRAIL availability for receptors like TRAIL-R1 and TRAIL-R2.

Transmembrane Domain (TMD):

• Like other TRAIL receptors, TNFRSF10D has a single transmembrane domain that anchors it in the cellular membrane, allowing it to interact with extracellular TRAIL ligands. This membrane-bound nature is important for its regulatory role in cell signaling.

Truncated Death Domain (DD):

• A defining feature of TNFRSF10D is its truncated death domain. While death domains are generally responsible for initiating apoptosis signaling through adaptor proteins (such as FADD), the truncated domain in TNFRSF10D lacks the complete structure necessary to recruit these apoptotic mediators effectively.
• This structural difference means that TNFRSF10D cannot form a functional death-inducing signaling complex (DISC), thus preventing apoptotic signaling in response to TRAIL binding. The truncated death domain distinguishes TNFRSF10D as a non-apoptotic receptor, focusing instead on regulatory and protective roles.

This structural combination allows TNFRSF10D to bind TRAIL similarly to its apoptotic counterparts but without transmitting an apoptotic signal, reinforcing its role as a “decoy” within TRAIL signaling pathways.

Classification and Subtypes

TNFRSF10D is part of the TRAIL receptor family within the TNF receptor superfamily. This family includes other TRAIL-binding receptors such as TRAIL-R1 (TNFRSF10A), TRAIL-R2 (TNFRSF10B), and TRAIL-R3 (TNFRSF10C). The key classification of TRAIL receptors is based on their ability to signal apoptosis:

Apoptotic Receptors:

• TRAIL-R1 and TRAIL-R2 contain intact death domains and are capable of inducing apoptosis upon binding with TRAIL, which is essential in targeting cancer cells.

Decoy Receptors:

• TNFRSF10C and TNFRSF10D are classified as decoy receptors due to their inability to initiate apoptosis. TNFRSF10D’s truncated death domain and TNFRSF10C’s lack of an intracellular domain altogether prevent them from transducing apoptotic signals, enabling them to function primarily as modulators in TRAIL signaling.

There are no known subtypes or variants within TNFRSF10D.

Function and Biological Significance

Modulation of Apoptosis:

• The primary function of TNFRSF10D is to act as a decoy receptor that can bind TRAIL without triggering apoptosis. By competing for TRAIL binding, TNFRSF10D helps regulate the availability of TRAIL for apoptotic receptors, effectively modulating cell sensitivity to TRAIL-induced cell death.
• This protective role is particularly relevant in normal, non-transformed cells, where TNFRSF10D expression is higher. By limiting apoptotic signaling in these cells, TNFRSF10D contributes to the preservation of healthy tissue integrity.

Role in Immune Surveillance:

• TRAIL is involved in immune system activities, particularly in identifying and removing cancerous or infected cells. TNFRSF10D’s presence in normal tissues serves as a checkpoint mechanism that selectively targets TRAIL signaling towards abnormal cells, thereby protecting non-transformed cells from unintended immune-mediated apoptosis.

Influence in Cancer:

• In cancer biology, TNFRSF10D can play a dual role. On one hand, it provides a protective function in healthy cells. On the other hand, upregulation of TNFRSF10D in certain cancer types may contribute to tumor resistance against TRAIL-based treatments. Cancer cells expressing high levels of TNFRSF10D are less susceptible to TRAIL-induced apoptosis, as TRAIL binding is inhibited from reaching apoptosis-inducing receptors.

Clinical Issues

Implications in Cancer Therapy:

• TNFRSF10D’s function as a decoy receptor has clinical implications for TRAIL-based cancer therapies. Tumors with elevated expression of TNFRSF10D are more resistant to TRAIL-induced apoptosis, posing challenges for using TRAIL as a therapeutic agent in these contexts.
• Research efforts are focused on overcoming this resistance by either targeting TNFRSF10D specifically or developing TRAIL variants or agonists that preferentially engage with TRAIL-R1 and TRAIL-R2, bypassing TNFRSF10D-mediated inhibition.

Role in Autoimmunity and Inflammation:

• In autoimmune diseases, TNFRSF10D’s modulation of apoptosis in immune cells is significant. TRAIL signaling plays a role in regulating immune cell lifespan and in maintaining immune tolerance by removing autoreactive cells. TNFRSF10D’s decoy function could influence this process, potentially affecting immune homeostasis.
• Targeting TNFRSF10D therapeutically could provide a strategy for modulating apoptosis in inflammatory and autoimmune diseases, either by enhancing or reducing TRAIL sensitivity as needed to restore immune balance.

Viral Infections:

• Certain viruses can exploit TNFRSF10D upregulation in host cells to evade immune detection and apoptosis. By increasing TNFRSF10D expression, infected cells may become resistant to immune-mediated cell death, facilitating viral persistence. Targeting TNFRSF10D in the context of viral infections is being investigated as a way to improve immune clearance of infected cells.

Summary

TNFRSF10D, or TRAIL-R4, is a decoy receptor within the TNF receptor superfamily that binds TRAIL but does not initiate apoptosis due to its truncated death domain. It plays a crucial role in modulating TRAIL-induced apoptosis, particularly in non-transformed cells, by competing for TRAIL binding and preventing excess apoptosis in healthy tissues. This protective mechanism is vital in immune surveillance, ensuring that TRAIL-induced cell death is primarily targeted toward abnormal or infected cells rather than normal tissues.

In cancer, TNFRSF10D expression may provide tumors with a means to resist TRAIL-induced apoptosis, creating challenges for TRAIL-based therapies. TNFRSF10D’s role in immune regulation also extends to autoimmune and inflammatory conditions, where its influence on TRAIL signaling can impact immune tolerance and inflammation. Additionally, certain viruses may manipulate TNFRSF10D to evade immune responses, further emphasizing its biological significance.

Therapeutic strategies to counteract TNFRSF10D-mediated resistance, particularly in cancer and viral infections, are ongoing. Understanding and leveraging TNFRSF10D’s decoy function holds promise for improving TRAIL-based cancer treatments and modulating immune responses in a range of diseases.