TNFSF10

Official Full Name

TNF superfamily member 10

Organism

Homo sapiens

GeneID

8743

Background

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein preferentially induces apoptosis in transformed and tumor cells, but does not appear to kill normal cells although it is expressed at a significant level in most normal tissues. This protein binds to several members of TNF receptor superfamily including TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and possibly also to TNFRSF11B/OPG. The activity of this protein may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and TNFRSF11B/OPG that cannot induce apoptosis. The binding of this protein to its receptors has been shown to trigger the activation of MAPK8/JNK, caspase 8, and caspase 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

Synonyms

TL2; APO2L; CD253; TANCR; TRAIL; Apo-2L; TNLG6A;

Bio Chemical Class

Cytokine: tumor necrosis factor

Protein Sequence

MAMMEVQGGPSLGQTCVLIVIFTVLLQSLCVAVTYVYFTNELKQMQDKYSKSGIACFLKEDDSYWDPNDEESMNSPCWQVKWQLRQLVRKMILRTSEETISTVQEKQQNISPLVRERGPQRVAAHITGTRGRSNTLSSPNSKNEKALGRKINSWESSRSGHSFLSNLHLRNGELVIHEKGFYYIYSQTYFRFQEEIKENTKNDKQMVQYIYKYTSYPDPILLMKSARNSCWSKDAEYGLYSIYQGGIFELKENDRIFVSVTNEHLIDMDHEASFFGAFLVG

Open

Disease

Brain cancer, Colorectal cancer, Lung cancer, Malignant haematopoietic neoplasm, Prostate cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

1 +

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Detailed Information

The TNFSF10 gene, located on human chromosome 3q26, encodes a type II transmembrane protein belonging to the tumor necrosis factor (TNF) ligand superfamily, widely known as TRAIL (TNF-related apoptosis-inducing ligand). Alternative splicing generates multiple transcript variants, with the most prominent being the full-length form (NM_003810, 281 amino acids) and a shorter secreted isoform (NM_001190943, 65 amino acids). The full-length TRAIL protein contains a highly conserved C-terminal extracellular domain that mediates trimerization, a structural prerequisite for receptor binding and downstream signaling.

Structurally, each TRAIL monomer adopts a "jelly-roll" topology with two antiparallel β-sheets, forming a homotrimer through a distinctive sandwich-like fold. This configuration is similar to other TNF family members but provides a unique receptor-binding interface, critical for selective apoptosis induction.

Receptor Interactions and Selective Cytotoxicity

TRAIL's hallmark feature is its ability to selectively induce apoptosis in transformed or tumor cells while sparing normal cells. This selectivity is mediated by its interaction with five distinct receptors. Two death receptors (TRAILR1/TNFRSF10A and TRAILR2/TNFRSF10B) contain intact death domains (DDs), initiating apoptotic signaling cascades, whereas three decoy receptors (TRAILR3/TNFRSF10C, TRAILR4/TNFRSF10D, and OPG/TNFRSF11B) lack functional DDs and act as molecular "traps" that competitively bind TRAIL, modulating its activity. Tumor cells often overexpress death receptors and underexpress decoy receptors, creating a molecular basis for TRAIL's tumor-selective cytotoxicity.

Signaling Pathways and Regulatory Mechanisms

Upon binding to death receptors TRAILR1 or TRAILR2, the receptor intracellular death domain recruits the adaptor protein FADD, which subsequently recruits and activates procaspase-8, forming the death-inducing signaling complex (DISC). Activated caspase-8 initiates apoptosis by directly activating effector caspases (caspase-3, -6, -7) and by cleaving Bid into tBid, which induces mitochondrial outer membrane permeabilization and cytochrome C release, amplifying the apoptotic signal. TRAIL can also engage MAPK8/JNK pathways, contributing to stress response regulation and apoptosis.

Notably, TRAIL can activate non-apoptotic pathways, including NF-κB and Akt, which may mediate pro-survival or pro-inflammatory effects, particularly in normal cells. Its activity is tightly regulated at multiple levels. Transcriptionally, interferons and inflammatory cytokines upregulate TRAIL expression. Post-translationally, zinc ions stabilize its trimeric structure, whereas certain cysteine proteases can generate soluble forms. Decoy receptors, either membrane-bound or soluble, limit activation of death receptors through competitive binding. Osteoprotegerin (OPG), initially identified as a RANKL antagonist, also binds TRAIL, particularly within the bone microenvironment, modulating its function. Intracellular inhibitors such as c-FLIP and IAPs further regulate TRAIL-induced apoptosis by interfering with DISC formation or caspase activity.

Figure 1. Molecular and Cellular Mechanisms of TRAIL resistance. (Deng D, et al., 2020)

Physiological and Pathological Roles

Under physiological conditions, TRAIL is widely expressed in tissues including the spleen, lung, prostate, and intestine, playing a key role in immune surveillance. TRAIL produced by activated T cells and NK cells helps eliminate transformed and virus-infected cells, maintaining tissue homeostasis. TRAIL-deficient mice display increased tumor susceptibility and higher spontaneous tumor incidence, confirming its role in tumor immune surveillance. TRAIL also contributes to immune tolerance, with deficiency linked to autoimmune disease development.

Pathologically, dysregulation of TRAIL signaling is implicated in multiple diseases. In vitiligo, an autoimmune skin disorder, the TNFSF10/hsa-let-7a-5p axis modulates autophagy and apoptosis, contributing to selective melanocyte loss. In oncology, while TRAIL selectively kills many tumor cells, certain cancers—such as undifferentiated thyroid carcinoma and colorectal adenocarcinoma—exhibit downregulated death receptors or upregulated decoy receptors, resulting in apoptotic resistance. Inflammatory factors within the tumor microenvironment can further shift TRAIL signaling toward tumor progression.

Clinical Translation and Therapeutic Potential

Capitalizing on TRAIL's tumor-selective apoptotic properties, recombinant TRAIL proteins (e.g., dulanermin) and agonistic antibodies targeting death receptors (e.g., mapatumumab for TRAILR1, lexatumumab for TRAILR2) have advanced into clinical trials. While demonstrating significant anti-tumor activity in vitro and in animal models, single-agent clinical efficacy remains limited due to intrinsic or acquired resistance and short in vivo half-life. Current strategies focus on novel drug delivery systems, such as nanoparticle carriers, and combination therapies with chemotherapy, targeted agents, or immune checkpoint inhibitors.

Overcoming resistance mechanisms has also been explored through natural compounds; for example, EGCG (epigallocatechin-3-gallate) from green tea and ginkgo can modulate TNFSF10 signaling to induce autophagy and apoptosis, showing potential in vitiligo therapy. Epigenetic modulators, such as histone deacetylase inhibitors, can upregulate death receptor expression to enhance TRAIL sensitivity. Gene therapy approaches, including oncolytic virus-mediated TRAIL delivery, aim to locally produce high TRAIL concentrations within tumors while eliciting antiviral immune responses.

As a disease biomarker, TRAIL and its receptor expression profiles provide prognostic value. High TRAILR1/R2 expression correlates with favorable outcomes in colorectal and non-small cell lung cancer, whereas high decoy receptor (TRAILR3/R4 or OPG) expression indicates poor prognosis. Circulating soluble TRAIL levels are elevated in autoimmune diseases such as SLE and rheumatoid arthritis, reflecting disease activity. Circulating exosomal TRAIL may serve as a non-invasive tumor biomarker, correlating with treatment response in melanoma and lung cancer patients.

Reference

Ion GND, Nitulescu GM, Popescu CI. Targeting TRAIL. Bioorg Med Chem Lett. 2019 Sep 15;29(18):2527-2534.
Deng D, Shah K. TRAIL of Hope Meeting Resistance in Cancer. Trends Cancer. 2020 Dec;6(12):989-1001.

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