TNFSF10 - TNF superfamily member 10 |Elisa - Clia - Antibody - Protein

Background

TNFSF10, also known as TRAIL (TNF-related apoptosis-inducing ligand), is a cytokine in the tumor necrosis factor (TNF) superfamily, known for its ability to induce apoptosis selectively in cancerous or infected cells. TRAIL is a type II transmembrane protein expressed by various immune cells, such as T cells, NK cells, and macrophages, and plays a pivotal role in immune surveillance and regulation. Unlike other TNF family ligands, TRAIL exhibits the unique ability to preferentially trigger cell death in transformed cells, sparing most normal cells. Its selective cytotoxicity has made it a significant target for cancer therapeutics and an area of research for treatments against viral infections and immune regulation.

TRAIL’s role in apoptosis is critical in regulating immune cell function, homeostasis, and tolerance, as it can trigger cell death through both extrinsic and intrinsic pathways. Due to this, TRAIL is an essential component of the immune response to abnormal or damaged cells and has garnered attention as a therapeutic target due to its ability to promote cell death in cancerous or infected cells with minimal toxicity to healthy tissues.

Protein Structure

TRAIL (TNFSF10) is a type II transmembrane protein that can also exist in a soluble form following cleavage. Its structure includes:

Intracellular Domain:

• The intracellular domain is relatively short and mainly functions in stabilizing the protein within the cell membrane.

Transmembrane Domain:

• TRAIL contains a transmembrane helix that anchors the molecule in the cell membrane. This domain is essential for maintaining its localization as a membrane-bound protein and for facilitating interactions with cell receptors.

Extracellular Domain:

• The extracellular region of TRAIL comprises approximately 200 amino acids and contains a TNF homology domain (THD), characteristic of other TNF family members. This domain is crucial for receptor binding and trimerization.
• TRAIL typically exists as a homotrimer in its functional form. The trimeric structure is essential for efficient interaction with death receptors (DR4 and DR5) on target cells, which initiates apoptotic signaling cascades.
• Glycosylation occurs on TRAIL’s extracellular domain, which enhances its stability and binding affinity to its receptors. Glycosylation is crucial for its function, as it affects the ligand's ability to activate downstream signaling.

Classification and Subtypes

TRAIL is classified as a member of the TNF superfamily, specifically TNFSF10. It is unique within this family for its receptor specificity and function:

Death Receptors (DR4 and DR5):

• TRAIL binds to DR4 (TRAIL-R1) and DR5 (TRAIL-R2), both of which contain death domains that are crucial for inducing apoptosis in the target cells. These receptors are expressed on a wide range of cells, including many cancer cells, but are generally absent or inactive in most normal cells, contributing to TRAIL’s selective cytotoxicity.

Decoy Receptors (DcR1 and DcR2):

• TRAIL also interacts with DcR1 (TRAIL-R3) and DcR2 (TRAIL-R4), known as decoy receptors. Unlike DR4 and DR5, these receptors do not contain functional death domains and therefore do not initiate apoptosis. Instead, they act as a buffer, binding to TRAIL and inhibiting its apoptotic function. DcR1 and DcR2 serve a regulatory role, protecting normal cells from unintended apoptosis by modulating TRAIL availability.

Soluble TRAIL:

• TRAIL can also be cleaved to generate a soluble form, which retains its trimeric structure and apoptotic function. Soluble TRAIL can circulate and exert its cytotoxic effects at distant sites, enhancing its role in immune surveillance and apoptotic regulation.

Function and Biological Significance

TRAIL’s primary function is to induce apoptosis selectively in abnormal cells, such as cancerous or virus-infected cells, contributing to immune surveillance and tumor suppression. It also plays significant roles in:

Apoptotic Signaling Pathway:

• TRAIL binds to DR4 and DR5, initiating the extrinsic apoptosis pathway. Upon binding, it recruits adapter proteins such as FADD (Fas-associated death domain), which activate caspases (e.g., caspase-8), the enzymes responsible for cell death. The caspase cascade can further engage the intrinsic apoptosis pathway through Bid cleavage, leading to mitochondrial dysfunction and the release of pro-apoptotic factors, amplifying the apoptotic response.

Immune Regulation:

• TRAIL is expressed by immune cells, including NK cells and cytotoxic T lymphocytes (CTLs), which use TRAIL-mediated apoptosis to eliminate infected or damaged cells. This function is critical in controlling viral infections and tumors, as it allows the immune system to selectively target abnormal cells without harming healthy tissues.

Regulation of Inflammation:

• TRAIL also plays a role in the resolution of inflammation by inducing apoptosis in activated immune cells, thus preventing prolonged immune activation. This function is important in maintaining immune homeostasis and preventing autoimmune responses.

Cancer Suppression:

• TRAIL’s selective apoptosis of cancer cells has garnered interest for its potential as a cancer therapeutic. TRAIL and its agonists are being developed to treat a variety of cancers, exploiting its ability to activate apoptosis in cells that are resistant to other forms of cell death.

Clinical Issues

Dysregulation of TRAIL and its receptors is associated with various diseases, including cancer, autoimmune diseases, and viral infections:

Cancer:

• Many cancer cells exhibit resistance to TRAIL-induced apoptosis through various mechanisms, such as downregulation of DR4 and DR5 or overexpression of anti-apoptotic proteins like c-FLIP and Bcl-2. To overcome resistance, TRAIL-based therapies are combined with other agents, such as chemotherapy or immunotherapy, to enhance TRAIL’s effectiveness in inducing apoptosis in cancer cells.

Autoimmune Disorders:

• In autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis, TRAIL dysregulation has been observed. TRAIL may contribute to immune cell death dysregulation in these conditions, and therapies targeting TRAIL signaling are being investigated to modulate immune responses and prevent tissue damage.

Infectious Diseases:

• TRAIL is essential for antiviral immune responses; however, some viruses have evolved mechanisms to inhibit TRAIL-induced apoptosis, allowing them to evade immune clearance. Research on TRAIL’s role in viral infections, including HIV and hepatitis, aims to harness TRAIL pathways for antiviral therapies.

Drug Development Challenges:

• Although TRAIL’s selective apoptosis in tumor cells makes it an attractive target for cancer treatment, its therapeutic application faces challenges. Soluble TRAIL and TRAIL receptor agonists exhibit limited efficacy in some clinical trials, attributed to short half-life, limited tumor targeting, and resistance mechanisms in cancer cells. Researchers are developing modified TRAIL variants, nanoparticle delivery systems, and combination therapies to overcome these limitations.

Summary

TNFSF10 (TRAIL) is a unique member of the TNF superfamily, with the distinct function of inducing apoptosis primarily in cancerous and infected cells while sparing normal cells. Structurally, TRAIL is a type II transmembrane protein with an extracellular TNF homology domain that enables trimerization and binding to death receptors DR4 and DR5, which initiate apoptotic signaling cascades upon activation. TRAIL also binds to decoy receptors, DcR1 and DcR2, which lack death domains and serve to regulate its apoptotic function in normal cells.

TRAIL’s role in immune regulation, cancer suppression, and viral defense underscores its biological importance. Clinically, TRAIL has emerged as a target for cancer therapies due to its ability to selectively induce apoptosis in malignant cells. However, resistance mechanisms in cancer cells and challenges in achieving effective drug delivery have limited its success as a monotherapy. Consequently, TRAIL-based treatments are being explored in combination with other therapeutic agents.

Research into TRAIL's role in autoimmune diseases, viral infections, and cancer continues to expand, with the goal of leveraging its apoptotic functions to develop safe and effective therapies. Further advancements in understanding TRAIL’s mechanisms of action and overcoming resistance will determine its success in clinical applications and broaden its therapeutic potential.