TNFSF10 TNF superfamily member 10 [Homo sapiens (human)] - Gene

Summary

Official Symbol: TNFSF10provided by HGNC
Official Full Name: TNF superfamily member 10provided by HGNC
Primary source: HGNC:HGNC:11925
See related: Ensembl:ENSG00000121858 MIM:603598
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: TL2; APO2L; CD253; TRAIL; Apo-2L; TNLG6A
Summary: 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]
Expression: Ubiquitous expression in lung (RPKM 64.9), placenta (RPKM 44.9) and 21 other tissues See more
Orthologs: mouse all

Genomic context

Location:: 3q26.31

Exon count:: 6

Annotation release	Status	Assembly	Chr	Location
109.20190905	current	GRCh38.p13 (GCF_000001405.39)	3	NC_000003.12 (172505508..172523430, complement)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	3	NC_000003.11 (172223298..172241297, complement)

Chromosome 3 - NC_000003.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

The downregulation of TXNDC5 could contribute to rheumatoid arthritis synovial fibroblasts antiangiogenic and proapoptotic features through suppression of CXCL10 and TRAIL.
Title: CXCL10 and TRAIL Are Upregulated by TXNDC5 in Rheumatoid Arthritis Fibroblast-like Synoviocytes.
these findings suggest that GADD34 inhibits TRAIL-induced HCC cell apoptosis through TRAF6- and ERK-mediated stabilization of MCL-1.
Title: The regulatory protein GADD34 inhibits TRAIL-induced apoptosis via TRAF6/ERK-dependent stabilization of myeloid cell leukemia 1 in liver cancer cells.
GroEL/ES mediated the in vivo recovery of TRAIL inclusion bodies in Escherichia coli.
Title: GroEL/ES mediated the in vivo recovery of TRAIL inclusion bodies in Escherichia coli.
In this review, we tried to collect and examine investigations that researchers have been able to sensitize cancer cells to TRAIL through targeting of c-FLIP alone or with other intracellular anti-apoptotic proteins directly or indirectly.
Title: Down-regulation of intracellular anti-apoptotic proteins, particularly c-FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL.
Data show that the diagnostic ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to identify an elevated HbF was significantly higher than that of the CD95 (Fas).
Title: Fas and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Are Closely Linked to the Levels of Glycated and Fetal Hemoglobin in Patients with Diabetes Mellitus.
Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells.
Title: Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells.
Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy.
Title: Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment.
data demonstrated a novel effect on TRAIL sensitivity on monocytes and monocytic leukemia cells of IL-4 and suggested that it may be necessary to reconsider the impact of current therapies against IL-4, JAK/STAT, and PI3K/Akt pathways with regard to TRAIL sensitivity
Title: Interleukin-4 Enhances the Sensitivity of Human Monocytes to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Through Upregulation of Death Receptor 4.
The results provide evidence for the differential impact of fucosylation on signaling via DR4 or DR5. The findings provide novel opportunities to enhance TRAIL sensitivity in colon adenocarcinoma cells that are highly resistant to DR5-mediated apoptosis.
Title: Death receptor 5 is activated by fucosylation in colon cancer cells.
TRAIL-induced activation of DcR2 led to increased NF-kappaB activation in large granular lymphocyte leukemia.
Title: TRAIL mediates and sustains constitutive NF-κB activation in LGL leukemia.

Submit: New GeneRIF Correction See all GeneRIFs (760)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Protein interactions

Protein	Gene	Interaction	Pubs
Envelope surface glycoprotein gp120	env	Treatment of HIV-1 Env-pseudotyped virus-infected MDM cells with both soluble TRAIL and an agonistic anti-DR5 antibody AD5-10 induces activation of caspase-3, -8, and -9	PubMed
	env	Treatment of CD4+ T cells with HIV-1 gp120 results in the upregulation of TRAIL death receptor expression and acquired sensitivity to TRAIL mediated cell death; this effect of gp120 requires the chemokine coreceptor CXCR4, but not CCR5 or the CD4 receptor	PubMed
	env	Treatment of human monocytes and primary neutrophils with N36 peptide from HIV-1 gp41 and F peptide from HIV-1 envelope protein gp120 increases endogenous tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression	PubMed
Envelope transmembrane glycoprotein gp41	env	Treatment of human monocytes and primary neutrophils with N36 peptide from HIV-1 gp41 and F peptide from HIV-1 envelope protein gp120 increases endogenous tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression	PubMed
Tat	tat	Microarray analysis indicates HIV-1 Tat-induced upregulation of tumor necrosis factor (ligand) superfamily, member 10 (TNFSF10; TRAIL) in primary human brain microvascular endothelial cells	PubMed
	tat	HIV-1 and the viral protein Tat modulate the expression of tumor necrosis factor (ligand) superfamily, member 10 (TNFSF10; TRAIL) in immature dendritic cells and monocyte-derived macrophages	PubMed
	tat	Microarray analysis indicates HIV-1 Tat upregulates the interferon-responsive gene expression of many proteins, including TRAIL, in immature dendritic cells, an effect that likely facilitates the expansion of HIV-1 infection	PubMed
	tat	HIV-1 Tat inhibits apoptosis mediated by TRAIL in Jurkat T cells	PubMed
	tat	Upregulation of TRAIL by HIV-1 Tat induces bystander-mediated apoptosis in T cells	PubMed
Vif	vif	HIV-1 Vif downregulates the expression of tumor necrosis factor ligand superfamily, member 10 (TNFSF10) in Vif-expression T cells	PubMed
Vpr	vpr	HIV-1 Vpr upregulates the expression of TRAIL in human monocyte-derived dendritic cells	PubMed

Go to the HIV-1, Human Interaction Database

Pathways from BioSystems

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Apoptosis, organism-specific biosystem (from KEGG)
Apoptosis, organism-specific biosystemApoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled...
Apoptosis, organism-specific biosystem (from WikiPathways)
Apoptosis, organism-specific biosystemApoptosis is a distinct form of cell death that is functionally and morphologically different from necrosis. Nuclear chromatin condensation, cytoplasmic shrinking, dilated endoplasmic reticulum, and ...
Apoptosis, conserved biosystem (from KEGG)
Apoptosis, conserved biosystemApoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled...
Apoptosis, organism-specific biosystem (from REACTOME)
Apoptosis, organism-specific biosystemApoptosis is a distinct form of cell death that is functionally and morphologically different from necrosis. Nuclear chromatin condensation, cytoplasmic shrinking, dilated endoplasmic reticulum, and ...
Apoptosis Modulation and Signaling, organism-specific biosystem (from WikiPathways)
Apoptosis Modulation and Signaling, organism-specific biosystemApoptosis, or cell death program, can be activated by various mechanisms within the extrinsic and the intrinsic pathway. While activation of cell death receptors leads to the engagement of the extrin...
CASP8 activity is inhibited, organism-specific biosystem (from REACTOME)
CASP8 activity is inhibited, organism-specific biosystemCell death triggered by extrinsic stimuli via death receptors or toll-like receptors (e.g., TLR3, TLR4) may result in either apoptosis or regulated necrosis (necroptosis) (Holler N et al. 2000; Kalai...
Caspase activation via extrinsic apoptotic signalling pathway, organism-specific biosystem (from REACTOME)
Caspase activation via extrinsic apoptotic signalling pathway, organism-specific biosystemKnown as the "death receptor pathway" the extrinsic or caspase 8/10 dependent pathway is activated by ligand binding. The "death receptors" are specialized cell-surface receptors including Fas/CD95, ...
Cytokine-cytokine receptor interaction, organism-specific biosystem (from KEGG)
Cytokine-cytokine receptor interaction, organism-specific biosystemCytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell ...
Cytokine-cytokine receptor interaction, conserved biosystem (from KEGG)
Cytokine-cytokine receptor interaction, conserved biosystemCytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell ...
Death Receptor Signalling, organism-specific biosystem (from REACTOME)
Death Receptor Signalling, organism-specific biosystemThe death receptors, all cell-surface receptors, begin the process of caspase activation. The common feature of these type 1 transmembrane proteins is the "death-domain" a conserved cytoplasmic motif...
Dimerization of procaspase-8, organism-specific biosystem (from REACTOME)
Dimerization of procaspase-8, organism-specific biosystemProcaspase-8 monomers undergo dimerization. The dimerization event occurs at death-inducing signaling complex (DISC) and results in a reposition of the procaspase-8 inter-subunit linker to become acc...
FoxO signaling pathway, organism-specific biosystem (from KEGG)
FoxO signaling pathway, organism-specific biosystemThe forkhead box O (FOXO) family of transcription factors regulates the expression of genes in cellular physiological events including apoptosis, cell-cycle control, glucose metabolism, oxidative str...
Influenza A, organism-specific biosystem (from KEGG)
Influenza A, organism-specific biosystemInfluenza is a contagious respiratory disease caused by influenza virus infection. Influenza A virus is responsible for both annual seasonal epidemics and periodic worldwide pandemics. Novel strains ...
Influenza A, conserved biosystem (from KEGG)
Influenza A, conserved biosystemInfluenza is a contagious respiratory disease caused by influenza virus infection. Influenza A virus is responsible for both annual seasonal epidemics and periodic worldwide pandemics. Novel strains ...
Ligand-dependent caspase activation, organism-specific biosystem (from REACTOME)
Ligand-dependent caspase activation, organism-specific biosystemCaspase-8 is synthesized as zymogen (procaspase-8) and is formed from procaspase-8 as a cleavage product. However, the cleavage itself appears not to be sufficient for the formation of an active casp...
Measles, organism-specific biosystem (from KEGG)
Measles, organism-specific biosystemMeasles virus (MV) is highly contagious virus that leads infant death worldwide. Humans are the unique natural reservoir for this virus. It causes severe immunosuppression favouring secondary bacteri...
Measles, conserved biosystem (from KEGG)
Measles, conserved biosystemMeasles virus (MV) is highly contagious virus that leads infant death worldwide. Humans are the unique natural reservoir for this virus. It causes severe immunosuppression favouring secondary bacteri...
Natural killer cell mediated cytotoxicity, organism-specific biosystem (from KEGG)
Natural killer cell mediated cytotoxicity, organism-specific biosystemNatural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stre...
Natural killer cell mediated cytotoxicity, conserved biosystem (from KEGG)
Natural killer cell mediated cytotoxicity, conserved biosystemNatural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stre...
Photodynamic therapy-induced AP-1 survival signaling., organism-specific biosystem (from WikiPathways)
Photodynamic therapy-induced AP-1 survival signaling., organism-specific biosystemPhotodynamic therapy may induce an acute stress response mediated by mitogen-activated protein kinase kinase kinase 5 (MAP3K5), its downstream MAPKs that target c-Jun N-terminal kinase (JNK, MAPK8) a...
Programmed Cell Death, organism-specific biosystem (from REACTOME)
Programmed Cell Death, organism-specific biosystemCell death is a fundamental cellular response that has a crucial role in shaping our bodies during development and in regulating tissue homeostasis by eliminating unwanted cells. There are a number o...
RIPK1-mediated regulated necrosis, organism-specific biosystem (from REACTOME)
RIPK1-mediated regulated necrosis, organism-specific biosystemReceptor-interacting kinase protein 1 (RIPK1) and RIPK3-dependent necrosis is called necroptosis or programmed necrosis. The kinase activities of RIPK1 and RIPK3 are essential for the necroptotic cel...
Regulated Necrosis, organism-specific biosystem (from REACTOME)
Regulated Necrosis, organism-specific biosystemNecrosis has traditionally been considered as a passive, unregulated cell death. However, accumulating evidence suggests that necrosis, like apoptosis, can be executed by genetically controlled and h...
Regulation by c-FLIP, organism-specific biosystem (from REACTOME)
Regulation by c-FLIP, organism-specific biosystemc-FLIP proteins (CASP8 and FADD-like apoptosis regulators or c-FLICE inhibitory proteins) are death effector domain (DED)-containing proteins that are recruited to the death-inducing signaling comple...
Regulation of necroptotic cell death, organism-specific biosystem (from REACTOME)
Regulation of necroptotic cell death, organism-specific biosystemA regulated balance between cell survival and cell death is essential for normal development and homeostasis of multicellular organisms. Defects in control of this balance may contribute to autoimmu...
Signal Transduction, organism-specific biosystem (from REACTOME)
Signal Transduction, organism-specific biosystemSignal transduction is a process in which extracellular signals elicit changes in cell state and activity. Transmembrane receptors sense changes in the cellular environment by binding ligands, such a...
TP53 Network, organism-specific biosystem (from WikiPathways)
TP53 Network, organism-specific biosystemP53 is not a lonely genome guardian, it operates with the assistance of p73 and p63 within a complex network including distinct but complementary pathways. This protein family presents a high le...
TRAIL signaling, organism-specific biosystem (from REACTOME)
TRAIL signaling, organism-specific biosystemTumor necrosis factor-related apoptosis-inducing ligand or Apo 2 ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family. This group of apoptosis induction pathways all work throug...
TRAIL signaling pathway, organism-specific biosystem (from Pathway Interaction Database)
TRAIL signaling pathway, organism-specific biosystem
TRAIL signaling pathway

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

TNFSF10_266 (e-PCR)
- UniSTS:277832

SHGC-77549 (e-PCR)
- UniSTS:16727

RH66570 (e-PCR)
- UniSTS:45442

Homology

Homologs of the TNFSF10 gene: The TNFSF10 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.
Orthologs from Annotation Pipeline: 238 organisms have orthologs with human gene TNFSF10
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
TRAIL binding	IEA Inferred from Electronic Annotation more info
cytokine activity	IEA Inferred from Electronic Annotation more info
identical protein binding	IDA Inferred from Direct Assay more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
signaling receptor binding	TAS Traceable Author Statement more info	PubMed
tumor necrosis factor receptor binding	IEA Inferred from Electronic Annotation more info
zinc ion binding	IDA Inferred from Direct Assay more info	PubMed

Process	Evidence Code	Pubs
activation of cysteine-type endopeptidase activity involved in apoptotic process	TAS Traceable Author Statement more info
apoptotic process	IEA Inferred from Electronic Annotation more info
cell surface receptor signaling pathway	TAS Traceable Author Statement more info
cell-cell signaling	TAS Traceable Author Statement more info	PubMed
immune response	IEA Inferred from Electronic Annotation more info
male gonad development	IEA Inferred from Electronic Annotation more info
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	TAS Traceable Author Statement more info
positive regulation of I-kappaB kinase/NF-kappaB signaling	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of I-kappaB kinase/NF-kappaB signaling	IEP Inferred from Expression Pattern more info	PubMed
positive regulation of apoptotic process	IDA Inferred from Direct Assay more info	PubMed
positive regulation of cysteine-type endopeptidase activity involved in apoptotic process	IDA Inferred from Direct Assay more info	PubMed
positive regulation of extrinsic apoptotic signaling pathway	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of extrinsic apoptotic signaling pathway	IDA Inferred from Direct Assay more info	PubMed
positive regulation of release of cytochrome c from mitochondria	IDA Inferred from Direct Assay more info	PubMed
regulation of extrinsic apoptotic signaling pathway via death domain receptors	TAS Traceable Author Statement more info
response to insulin	IEA Inferred from Electronic Annotation more info
signal transduction	TAS Traceable Author Statement more info	PubMed

Component	Evidence Code	Pubs
extracellular exosome	HDA more info	PubMed
extracellular region	TAS Traceable Author Statement more info
integral component of plasma membrane	TAS Traceable Author Statement more info	PubMed

General protein information

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Preferred Names: tumor necrosis factor ligand superfamily member 10

Names: Apo-2 ligand; TNF-related apoptosis inducing ligand TRAIL; chemokine tumor necrosis factor ligand superfamily member 10; tumor necrosis factor (ligand) family, member 10; tumor necrosis factor (ligand) superfamily, member 10; tumor necrosis factor apoptosis-inducing ligand splice variant delta; tumor necrosis factor ligand 6A; tumor necrosis factor superfamily member 10

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

NM_001190942.2 → NP_001177871.1 tumor necrosis factor ligand superfamily member 10 isoform 2

See identical proteins and their annotated locations for NP_001177871.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks two consecutive exons in the CDS, resulting in a frame-shift, as compared to variant 1. The resulting isoform (2) is shorter and has a different C-terminus, as compared to isoform 1.

Source sequence(s)

AC016938, AK296085

Consensus CDS

CCDS54680.1

UniProtKB/Swiss-Prot

P50591

Related

ENSP00000389931.2, ENST00000420541.6
NM_001190943.2 → NP_001177872.1 tumor necrosis factor ligand superfamily member 10 isoform 3

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks multiple 3' exons, but has an alternate 3' exon, as compared to variant 1. The resulting isoform (3) is very short and has a different C-terminus, as compared to isoform 1.

Source sequence(s)

AC007919, AC016938
NM_003810.4 → NP_003801.1 tumor necrosis factor ligand superfamily member 10 isoform 1

See identical proteins and their annotated locations for NP_003801.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longest isoform (1).

Source sequence(s)

AC007919, AC016938

Consensus CDS

CCDS3219.1

UniProtKB/Swiss-Prot

P50591

UniProtKB/TrEMBL

Q6IBA9

Related

ENSP00000241261.2, ENST00000241261.7

Conserved Domains (1) summary

pfam00229
Location:153 → 280

TNF; TNF(tumor Necrosis Factor) family

RNA

NR_033994.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (4) lacks an internal exon in the CDS, resulting in frame-shift and a premature translation termination, as compared to variant 1. The transcript is a nonsense-mediated mRNA decay candidate.

Source sequence(s)

AC016938, DA041872