TNFRSF10A - TNF receptor superfamily member 10a | Elisa - Clia - Antibody - Protein

Background

TNFRSF10A (TNF receptor superfamily member 10a), also known as TRAIL receptor 1 (TRAIL-R1) or death receptor 4 (DR4), is a member of the TNF receptor superfamily. TNFRSF10A is primarily recognized for its ability to bind to TRAIL (TNF-related apoptosis-inducing ligand), a pro-apoptotic ligand that induces cell death selectively in transformed or cancerous cells. TRAIL and its receptors are part of a critical signaling axis that regulates apoptosis, especially in response to cellular stress and immune-mediated cell targeting. The receptor is expressed on the cell surface of a variety of tissues and has been implicated in numerous physiological processes, including tumor surveillance, immune response, and inflammatory regulation. Due to its ability to mediate apoptosis in abnormal cells while sparing normal cells, TNFRSF10A has gained attention in cancer research as a therapeutic target.

Protein Structure

The TNFRSF10A protein is a type I transmembrane receptor and contains several key structural features:

Extracellular Domain:

• TNFRSF10A has an extracellular cysteine-rich domain (CRD) characteristic of TNF receptor family members. The CRD, organized into three subdomains (CRD1, CRD2, and CRD3), is responsible for ligand binding. This domain contains multiple disulfide bonds that provide structural stability and contribute to the proper conformation for interaction with TRAIL.
• Ligand binding occurs when TRAIL forms homotrimers, which then interact with three receptor molecules, forming a ligand-receptor complex that promotes the clustering of TNFRSF10A molecules and initiates downstream signaling.

Transmembrane Domain:

• This single-pass transmembrane domain anchors the receptor within the cell membrane, ensuring proper localization and accessibility for TRAIL binding. The transmembrane domain is hydrophobic and spans the lipid bilayer, providing structural integrity for TNFRSF10A’s role as a signaling receptor.

Intracellular Death Domain:

• The intracellular death domain (DD) is a conserved region essential for signaling apoptosis. The death domain interacts with downstream adaptor proteins such as FADD (Fas-associated protein with death domain). Upon TRAIL binding, multiple TNFRSF10A receptors oligomerize, forming a complex that recruits FADD and other downstream effectors necessary for activating the extrinsic apoptosis pathway.
• This death domain is critical for transmitting apoptotic signals, as it engages with components of the death-inducing signaling complex (DISC) upon ligand binding, initiating the cascade that ultimately activates caspases and promotes programmed cell death.

Classification and Subtypes

TNFRSF10A is part of the TNF receptor superfamily, a group characterized by their shared structural domains and roles in apoptosis, cell survival, and immune modulation. Within this superfamily, TNFRSF10A specifically belongs to the subgroup of death receptors, defined by their ability to directly induce apoptosis through intracellular death domains. There are no subtypes of TNFRSF10A, but it is closely related to TNFRSF10B (TRAIL-R2 or DR5), another receptor that also binds TRAIL and can mediate apoptosis. Both TNFRSF10A and TNFRSF10B are functional TRAIL receptors capable of inducing cell death, while additional receptors like DcR1 and DcR2 lack functional death domains and serve as decoy receptors, modulating TRAIL signaling without inducing apoptosis.

Function and Biological Significance

Apoptosis and Cell Death:

• TNFRSF10A plays a fundamental role in apoptosis, particularly in immune surveillance and tumor suppression. Upon TRAIL binding, TNFRSF10A oligomerizes, leading to the recruitment of FADD and activation of caspase-8. This cascade then activates downstream effector caspases such as caspase-3 and caspase-7, leading to cell death.
• The receptor's ability to selectively induce apoptosis in malignant or virus-infected cells while sparing normal cells is significant for immune homeostasis and protection against malignancy.

Immune Regulation:

• Beyond apoptosis, TNFRSF10A contributes to immune responses by promoting the elimination of damaged or infected cells. This function is vital for immune system homeostasis and helps control chronic infections and autoimmunity.
• TNFRSF10A’s selective apoptotic effects are enhanced by cytokine regulation, wherein immune cells like NK cells and T cells express TRAIL to target cells presenting TNFRSF10A, leading to immune-mediated cytotoxicity.

Tumor Surveillance and Anti-Cancer Mechanisms:

• The receptor’s role in tumor surveillance has garnered attention in cancer immunotherapy. TNFRSF10A-mediated apoptosis is one mechanism by which the immune system can eliminate transformed cells, reducing tumor growth and metastasis.
• TRAIL signaling through TNFRSF10A is a potential therapeutic pathway for cancers that express the receptor, as drugs or recombinant TRAIL variants targeting TNFRSF10A can induce apoptosis specifically in tumor cells.

Clinical Issues

Cancer Therapy:

• Because TNFRSF10A selectively induces apoptosis in cancer cells, it has become a target in cancer therapy. Recombinant TRAIL, agonistic antibodies, and small molecules that stimulate TNFRSF10A have been investigated in clinical trials for their ability to target and kill tumor cells.
• Resistance to TRAIL-based therapies can occur due to mutations in the death domain, altered expression of decoy receptors (DcR1, DcR2), or upregulation of anti-apoptotic proteins (e.g., c-FLIP, Bcl-2). Overcoming this resistance is a primary challenge in enhancing the efficacy of TNFRSF10A-targeted cancer therapies.

Autoimmune Diseases:

• Dysregulation of TRAIL and TNFRSF10A signaling has been implicated in autoimmune diseases, where excessive apoptosis can damage normal tissues, or insufficient apoptosis allows for the survival of autoreactive immune cells.
• Understanding TNFRSF10A signaling in immune tolerance and autoimmunity could provide insights into therapeutic interventions to restore balanced immune responses in autoimmune conditions.

Viral Infections:

• Certain viruses can interfere with TNFRSF10A signaling as a strategy to evade immune clearance. By downregulating receptor expression or blocking TRAIL-mediated apoptosis, these viruses persist in the host, contributing to chronic infections.
• Targeting TNFRSF10A signaling pathways in viral infections could enhance immune clearance, reducing viral load and improving patient outcomes.

Summary

TNFRSF10A, or TRAIL-R1, is a critical member of the TNF receptor superfamily, acting primarily as a death receptor that induces apoptosis through TRAIL binding. Its trimeric extracellular domain allows high-affinity binding to TRAIL, while its intracellular death domain initiates apoptosis via caspase activation. This receptor plays an essential role in immune regulation, tumor surveillance, and inflammation by selectively inducing apoptosis in abnormal cells, making it a promising therapeutic target, particularly in cancer. However, resistance mechanisms and dysregulated signaling present challenges, and research continues to refine therapeutic approaches involving TNFRSF10A for both oncology and immunology.

In sum, TNFRSF10A’s structure and function are central to its role in promoting apoptosis, with significant potential in targeted cancer therapies. Additionally, its implications in autoimmune diseases and viral persistence highlight its broader relevance in immune regulation.