TNFSF10

Summary

TNFSF10 (TNF superfamily member 10, HGNC:11925) is a protein-coding gene on chromosome 3q26.31, encoding Tumor necrosis factor ligand superfamily member 10 (P50591). Cytokine that binds to TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and possibly also to TNFRSF11B/OPG.

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.

Source: NCBI Gene 8743 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 57 total
• Druggable target: yes
• MANE Select transcript: NM_003810

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11925
Approved symbol	TNFSF10
Name	TNF superfamily member 10
Location	3q26.31
Locus type	gene with protein product
Status	Approved
Aliases	TRAIL, Apo-2L, TL2, CD253, TANCR
Ensembl gene	ENSG00000121858
Ensembl biotype	protein_coding
OMIM	603598
Entrez	8743

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000241261, ENST00000420541, ENST00000430881, ENST00000466777, ENST00000472804, ENST00000494851, ENST00000855868, ENST00000855869, ENST00000855870, ENST00000855871, ENST00000855872, ENST00000967485

RefSeq mRNA: 3 — MANE Select: NM_003810 NM_001190942, NM_001190943, NM_003810

CCDS: CCDS3219, CCDS54680

Canonical transcript exons

ENST00000241261 — 5 exons

Exon	Start	End
ENSE00001858222	172505508	172506919
ENSE00001929619	172523253	172523430
ENSE00003476464	172509217	172509321
ENSE00003561514	172514861	172514998
ENSE00003640658	172511617	172511659

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 99.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 36.2202 / max 3391.4171, expressed in 981 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45632	25.4085	814
45633	10.6643	843
45634	0.1276	4
45635	0.0197	2

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
nasal cavity epithelium	UBERON:0005384	99.57	gold quality
urethra	UBERON:0000057	99.14	gold quality
monocyte	CL:0000576	98.93	gold quality
mononuclear cell	CL:0000842	98.87	gold quality
bronchial epithelial cell	CL:0002328	98.86	gold quality
leukocyte	CL:0000738	98.82	gold quality
jejunal mucosa	UBERON:0000399	98.75	gold quality
epithelium of bronchus	UBERON:0002031	98.75	gold quality
bronchus	UBERON:0002185	98.75	gold quality
palpebral conjunctiva	UBERON:0001812	98.67	gold quality
renal medulla	UBERON:0000362	98.47	gold quality
nasal cavity mucosa	UBERON:0001826	98.46	gold quality
rectum	UBERON:0001052	98.30	gold quality
lower lobe of lung	UBERON:0008949	98.21	gold quality
penis	UBERON:0000989	98.16	gold quality
pericardium	UBERON:0002407	98.15	gold quality
superior surface of tongue	UBERON:0007371	98.11	gold quality
mammary duct	UBERON:0001765	98.00	gold quality
minor salivary gland	UBERON:0001830	97.90	gold quality
epithelium of mammary gland	UBERON:0003244	97.89	gold quality
oral cavity	UBERON:0000167	97.84	gold quality
pylorus	UBERON:0001166	97.84	gold quality
duodenum	UBERON:0002114	97.84	gold quality
mouth mucosa	UBERON:0003729	97.82	gold quality
skin of hip	UBERON:0001554	97.68	gold quality
calcaneal tendon	UBERON:0003701	97.66	gold quality
mammalian vulva	UBERON:0000997	97.65	gold quality
upper leg skin	UBERON:0004262	97.63	gold quality
granulocyte	CL:0000094	97.57	gold quality
ileal mucosa	UBERON:0000331	97.55	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	3449.51
E-MTAB-10855	yes	1674.14
E-MTAB-9841	yes	1254.32
E-HCAD-1	yes	786.87
E-CURD-114	yes	66.91
E-HCAD-11	yes	40.91
E-GEOD-134144	yes	39.67
E-GEOD-135922	yes	38.69
E-HCAD-10	yes	30.19
E-CURD-88	yes	27.30
E-GEOD-81608	yes	15.09
E-CURD-112	yes	11.10
E-GEOD-83139	yes	10.67
E-MTAB-8498	yes	10.19
E-GEOD-130148	yes	6.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DLL4, DNMT3B, EGR1, ESR1, EZH2, FOSB, FOXO1, FOXO3, FOXO4, FUBP1, HDAC2, IL2, IRF1, IRF2, IRF3, IRF4, IRF5, IRF6, IRF7, IRF9, JUND, NAB2, NFATC1, NFATC2, NFATC3, NFATC4, NFIL3, NFKB1, NFKB, NFKBIA, NR4A2, PML, PPARA, PPARG, RBPJ, REL, RELA, RUNX1, RXRA, SMAD4

miRNA regulators (miRDB)

82 targeting TNFSF10, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981

Literature-anchored findings (GeneRIF, showing 40)

• crystal structure at 2.2 A resolution of a complex between TRAIL and the extracellular region of DR5 (PMID:10542098)
• Apo2 ligand mRNA levels increase following irradiation of human T lineage-derived tumor cells. Recombinant soluble Apo2L enhanced the lethality of therapeutic doses of irradiation, indicating their possible use in combination for clinical therapy. (PMID:11059770)
• The Apo2L gene spans ~ 20 kb and is composed of 5 exons. The 1.2-kb Apo2L promoter region upstream of the translation initiation codon was cloned, its transcription start site defined, and several putative transcription factor binding sites identified. (PMID:11095979)
• TNF-related apoptosis-inducing ligand (TRAIL) enhances T cell proliferation following T cell receptor engagement and signals the augmentation of IFN-gamma secretion via a p38 mitogen-activated protein kinase-dependent pathway. (PMID:11466352)
• Interferon-alpha and -beta, but not -gamma, induce apoptosis through Apo2 ligand transcriptional induction in multiple myeloma tumor cells and freshly derived primary cells. (PMID:11568006)
• Differential secretion of APO2 ligand microvesicles during activation-induced death of T cells (PMID:11739488)
• Up-regulation in highly malignant multiple myeloma plasma cells negatively regulates erythroblast maturation; a major pathogenetic mechanism of anemia in multiple myeloma. (PMID:11830480)
• TNF-related apoptosis-inducing ligand (TRAIL) is not constitutively expressed in the human brain, whereas both apoptosis-mediating and apoptosis-blocking TRAIL receptors are found on neurons, astrocytes, and oligodendrocytes (PMID:11844843)
• TRAIL/Apo2L-induced apoptosis is mediated by ROS-activated p38 MAP kinase followed by caspase activation in HeLa cells. (PMID:11852102)
• signaling pathway and intracellular regulation of TRAIL-induced apoptosis in multiple myeloma cells (PMID:11877293)
• Results suggest that IFN-gamma facilitates TRAIL-induced activation of mitochondria-regulated as well as mitochondria-independent apoptotic pathways in breast tumour cells. (PMID:11936954)
• An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis (PMID:11940602)
• Histone deacetylase inhibitors sensitize human colonic adenocarcinoma cell lines to TNF-related apoptosis inducing ligand-mediated apoptosis. (PMID:11956660)
• Apo-2L-induced processing of caspase-3,caspase-8, and Bid is significantly increased by overexpression of Smac/DIABLO. (PMID:11964312)
• Although it does not contribute to mechanisms of peripheral T cell tolerance such as clonal anergy or deletion by apoptosis, TRAIL can directly inhibit activation of human T cells via blockade of calcium influx. (PMID:11994437)
• XAF1 augments TRAIL-induced apoptosis (PMID:12029096)
• Stimulation of the mitogen-activated protein kinase pathway antagonizes TRAIL-induced apoptosis downstream of BID cleavage in human breast cancer MCF-7 cells. (PMID:12082620)
• TRAIL induced translocation of Bax after cleavage of Bid in parental cells but not mitochondrial-DNA-deficient cells. (PMID:12082629)
• APO2L/TRAIL, specifically induced by autologous tumor and up-regulated by IFN-alpha, is a key mediator of tumor-specific CD4+ cytotoxic T lymphocyte-mediated cell death. (PMID:12097384)
• TRAIL/Apo2L in combination with interferon-beta synergistically induces apoptosis and inhibits melanoma cell proliferation in vitro, at least in part by cleavage of the X-linked inhibitor of apoptosis (XIAP). (PMID:12097388)
• Data show that transfer of the gene encoding Smac sensitized tumor and malignant glioma cells for apoptosis, and that Smac peptides enhanced the antitumor activity of Apo-2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). (PMID:12118245)
• TRAIL gene expression regulation by PI3 kinase, Akt and GSK-3 in tumor cells (PMID:12140294)
• Caspase-10 is recruited to and activated at the native TRAIL death-inducing signalling complex in a FADD-dependent manner. (PMID:12198154)
• TRAIL is a direct target of FKHRL1 (PMID:12351634)
• induces apoptosis independently of the mitochondrial apoptosis mediator DAP3 (PMID:12359235)
• osteoblasts are resistant to Apo2L/TRAIL-mediated apoptosis (PMID:12398939)
• These results provide new insights into the mechanisms of bile acid cytotoxicity and the proapoptotic effects of cFLIP phosphorylation in TRAIL signaling. (PMID:12407100)
• The human papillomavirus type 16 E5 protein impairs TRAIL- and FasL-mediated apoptosis in HaCaT cells by different mechanisms. (PMID:12414956)
• Plasma cells synthesize TRAIL and are subject to TRAIL-mediated apoptosis, which correlates with inactivation of the CD40-NF-kappa B survival pathway. (PMID:12421926)
• Enhanced expression of TRAIL promotes peripheral blood eosinophil survival in the airways of allergic asthmatics following segmental antigen challenge. (PMID:12421985)
• T cells from systemic lupus erythematosus patients kill autologous monocytes through apoptotic pathways involving the ligand TRAIL. (PMID:12421989)
• Trail protein sensitivity and cell cycle phase; TRAIL preferentially induces apoptosis in tumor cells over normal cells. (PMID:12429913)
• soluble TRAIL in the HBV infected people may participate in the liver damage (PMID:12439929)
• The apoptosis-inducing TRAIL gene caused significant changes in the biomechanics properties of Jurkat cells. (PMID:12445619)
• NF-kappaB prevents TRAIL-induced apoptosis in human hepatoma through a TRAIL-activated TRAF2-NIK-IKK pathway. (PMID:12447876)
• TRAIL death pathway is present and can function in human islet beta cells. (PMID:12488957)
• TRAIL protein binds and induces oligomerization of its cell-membrane death receptors (DR4 and DR5). These trigger the activity of CASP8 and apoptosis through DISC. (PMID:12496482)
• The susceptibility of neutrophils to TRAIL-mediated apoptosis suggests a role for TRAIL in the regulation of inflammation and may provide a mechanism for clearance of neutrophils from sites of inflammation. (PMID:12517970)
• Localization of TRAIL/TRAILR in fetal pancreas. (PMID:12532461)
• c-FLIP(L) and c-FLIP(S) potently control TRAIL responses, both by distinct regulatory features, and further imply that the differentiation state of malignant cells determines their sensitivity to death receptor signals. (PMID:12556488)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnfsf10	ENSDARG00000057241
mus_musculus	Tnfsf10	ENSMUSG00000039304
rattus_norvegicus		ENSRNOG00000086118

Paralogs (8): CD40LG (ENSG00000102245), FASLG (ENSG00000117560), TNFSF11 (ENSG00000120659), TNFSF14 (ENSG00000125735), TNFSF15 (ENSG00000181634), LTA (ENSG00000226979), LTB (ENSG00000227507), TNF (ENSG00000232810)

Protein

Protein identifiers

Tumor necrosis factor ligand superfamily member 10 — P50591 (reviewed: P50591)

Alternative names: Apo-2 ligand, TNF-related apoptosis-inducing ligand

All UniProt accessions (3): P50591, H7C246, Q6IBA9

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that binds to TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and possibly also to TNFRSF11B/OPG. Induces apoptosis. Its activity may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4 and TNFRSF11B/OPG that cannot induce apoptosis.

Subunit / interactions. Homotrimer. One TNFSF10 homotrimer interacts with three TNFSF10A mononers. One TNFSF10 homotrimer interacts with three TNFSF10B mononers.

Subcellular location. Cell membrane. Secreted.

Tissue specificity. Widespread; most predominant in spleen, lung and prostate.

Post-translational modifications. Tyrosine phosphorylated by PKDCC/VLK.

Miscellaneous. Induced upon HIV infection, antagonizes signaling via TRAIL receptor R2 (TNFRSF10B).

Similarity. Belongs to the tumor necrosis factor family.

Isoforms (2)

UniProt ID	Names	Canonical?
P50591-1	1	yes
P50591-2	2, TRAIL-short, TRAIL-s

RefSeq proteins (2): NP_001177871, NP_003801* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006052	TNF_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR017355	TNF_ligand_10/11	Family
IPR021184	TNF_CS	Conserved_site

Pfam: PF00229

UniProt features (29 total): strand 13, turn 3, topological domain 2, sequence variant 2, splice variant 2, chain 1, transmembrane region 1, helix 1, domain 1, region of interest 1, compositionally biased region 1, binding site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
1DG6	X-RAY DIFFRACTION	1.3
1D4V	X-RAY DIFFRACTION	2.2
1DU3	X-RAY DIFFRACTION	2.2
1D0G	X-RAY DIFFRACTION	2.4
1D2Q	X-RAY DIFFRACTION	2.8
5CIR	X-RAY DIFFRACTION	3
4N90	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50591-F1	82.19	0.53

Antibody-complex structures (SAbDab): 1 — 4N90

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 230

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-140534	Caspase activation via Death Receptors in the presence of ligand
R-HSA-3371378	Regulation by c-FLIP
R-HSA-5213460	RIPK1-mediated regulated necrosis
R-HSA-5218900	CASP8 activity is inhibited
R-HSA-69416	Dimerization of procaspase-8
R-HSA-75158	TRAIL signaling

MSigDB gene sets: 529 (showing top): MODULE_92, BROWNE_HCMV_INFECTION_8HR_UP, MODULE_45, MODULE_64, GOZGIT_ESR1_TARGETS_DN, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, chr3q26, BOHN_PRIMARY_IMMUNODEFICIENCY_SYNDROM_DN, GOBP_POSITIVE_REGULATION_OF_RELEASE_OF_CYTOCHROME_C_FROM_MITOCHONDRIA, GOBP_CELL_CELL_SIGNALING, OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_UP, SMITH_TERT_TARGETS_DN, BENNETT_SYSTEMIC_LUPUS_ERYTHEMATOSUS

GO Biological Process (12): apoptotic process (GO:0006915), immune response (GO:0006955), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), cell-cell signaling (GO:0007267), TRAIL-activated apoptotic signaling pathway (GO:0036462), positive regulation of apoptotic process (GO:0043065), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of release of cytochrome c from mitochondria (GO:0090200), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), cell communication (GO:0007154), signaling (GO:0023052)

GO Molecular Function (9): signaling receptor binding (GO:0005102), cytokine activity (GO:0005125), tumor necrosis factor receptor binding (GO:0005164), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), TRAIL binding (GO:0045569), protein binding (GO:0005515), tumor necrosis factor receptor superfamily binding (GO:0032813), metal ion binding (GO:0046872)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Caspase activation via Death Receptors in the presence of ligand	2
Caspase activation via extrinsic apoptotic signalling pathway	1
Regulated Necrosis	1
Regulation of necroptotic cell death	1
Death Receptor Signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
cell communication	2
cellular process	2
signaling	2
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
immune system process	1
response to stimulus	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
extrinsic apoptotic signaling pathway via death domain receptors	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
release of cytochrome c from mitochondria	1
positive regulation of organelle organization	1
regulation of release of cytochrome c from mitochondria	1
extrinsic apoptotic signaling pathway	1
positive regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
regulation of biological process	1
receptor ligand activity	1
tumor necrosis factor receptor superfamily binding	1
transition metal ion binding	1
binding	1
cytokine receptor binding	1
cation binding	1
membrane	1
cell periphery	1
extracellular vesicle	1

Protein interactions and networks

STRING

2598 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFSF10	TNFRSF10A	O00220	999
TNFSF10	TNFRSF10B	O14763	999
TNFSF10	TNFRSF1A	P19438	993
TNFSF10	FAS	P25445	993
TNFSF10	TNFRSF10D	Q9UBN6	988
TNFSF10	TNFRSF25	P78507	960
TNFSF10	TNFRSF10C	O14798	956
TNFSF10	TNF	P01375	944
TNFSF10	FASLG	P48023	942
TNFSF10	TNFRSF11B	O00300	919
TNFSF10	FADD	Q13158	905
TNFSF10	CASP8	Q14790	865
TNFSF10	RIPK1	Q13546	803
TNFSF10	TNFRSF21	O75509	784
TNFSF10	CASP3	P42574	768

IntAct

56 interactions, top by confidence:

A	B	Type	Score
TNFRSF10B	TNFSF10	psi-mi:“MI:0407”(direct interaction)	0.950
TNFSF10	TNFRSF10B	psi-mi:“MI:0914”(association)	0.950
TNFSF10	TNFRSF10B	psi-mi:“MI:0407”(direct interaction)	0.950
TNFSF10	CASP8	psi-mi:“MI:0403”(colocalization)	0.920
TNFSF10	FADD	psi-mi:“MI:0914”(association)	0.910
TNFSF10	TNFRSF10A	psi-mi:“MI:0914”(association)	0.800
TNFRSF10A	TNFSF10	psi-mi:“MI:0407”(direct interaction)	0.800
TNFSF10	TNFRSF10C	psi-mi:“MI:0407”(direct interaction)	0.620
TNFRSF10D	TNFSF10	psi-mi:“MI:0407”(direct interaction)	0.620

BioGRID (46): TNFSF10 (Two-hybrid), PPP2CA (Affinity Capture-Western), CUL3 (Affinity Capture-Western), TNFRSF10B (Affinity Capture-Western), CASP8 (Affinity Capture-Western), FADD (Affinity Capture-Western), TNFRSF10B (Affinity Capture-Western), RIPK1 (Affinity Capture-Western), FADD (Affinity Capture-Western), CASP8 (Affinity Capture-Western), PEA15 (Affinity Capture-Western), CFLAR (Affinity Capture-Western), ACP5 (Two-hybrid), RBM48 (Two-hybrid), TNFSF10 (Co-crystal Structure)

ESM2 similar proteins: A1A5X5, A4IH36, D4AB34, O93449, O95150, O97605, O97626, P04088, P04924, P09529, P10600, P15203, P16047, P17125, P17491, P27093, P36939, P36940, P41047, P42917, P48023, P50591, P50592, P59694, P59695, P63306, P63307, P63308, Q04999, Q07258, Q5UBV8, Q5XIG2, Q6PGN1, Q80WL1, Q861W5, Q8BGU2, Q8BMF8, Q8IUK8, Q8K3Y7, Q8R2Z0

Diamond homologs: O43557, O95150, P09225, P10154, P26445, P36939, P36940, P41047, P41155, P48023, P50591, P63306, P63307, P63308, Q06332, Q06600, Q5UBV8, Q5WR07, Q861W5, Q8JFG3, Q8K3Y7, Q9BDN1, Q9BEA8, Q9XT48, O14788, O35235, P50592, Q9I8D8, Q9QYH9, Q9ESE2, P16599, Q75N23, Q9JM09, O35734, P01375, P04924, P19101, P29553, P33620, P51435

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
TNFSF10	up-regulates	TNFRSF10A	binding
TNFSF10	up-regulates	TNFRSF10B	binding
TNFRSF10C	down-regulates	TNFSF10	binding
NAB2	“down-regulates quantity by repression”	TNFSF10	“transcriptional regulation”
IL2	“down-regulates quantity by repression”	TNFSF10	“transcriptional regulation”
FUBP1	“down-regulates quantity by repression”	TNFSF10	“transcriptional regulation”
TNFSF10	“up-regulates quantity by expression”	NFKB1	“post transcriptional regulation”
TNFRSF10D	down-regulates	TNFSF10	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 18 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of apoptotic process	5	18.9×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

57 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	3
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

623 predictions. Top by Δscore:

Variant	Effect	Δscore
3:172509215:A:AC	donor_gain	1.0000
3:172509216:C:CC	donor_gain	1.0000
3:172515009:A:AC	acceptor_gain	0.9900
3:172515009:A:C	acceptor_gain	0.9900
3:172506920:C:CC	acceptor_gain	0.9800
3:172514855:ACCT:A	donor_loss	0.9800
3:172514856:CCTA:C	donor_loss	0.9800
3:172514857:CTA:C	donor_loss	0.9800
3:172514858:TACC:T	donor_loss	0.9800
3:172514859:A:C	donor_loss	0.9800
3:172514860:C:CA	donor_loss	0.9800
3:172515004:T:C	acceptor_gain	0.9800
3:172515004:T:TC	acceptor_gain	0.9800
3:172523248:CTGA:C	donor_loss	0.9800
3:172523249:TGACC:T	donor_loss	0.9800
3:172523250:GACC:G	donor_loss	0.9800
3:172509322:C:CC	acceptor_gain	0.9700
3:172523252:CCTG:C	donor_gain	0.9700
3:172506917:AGTCT:A	acceptor_loss	0.9600
3:172506918:GTC:G	acceptor_loss	0.9600
3:172506919:TCTG:T	acceptor_loss	0.9600
3:172506921:T:C	acceptor_loss	0.9600
3:172506918:GT:G	acceptor_gain	0.9500
3:172509200:T:C	donor_gain	0.9500
3:172514999:C:CC	acceptor_gain	0.9500
3:172507366:G:A	donor_gain	0.9400
3:172514995:GCAT:G	acceptor_loss	0.9400
3:172514997:ATCT:A	acceptor_gain	0.9400
3:172514998:TC:T	acceptor_loss	0.9400
3:172514999:C:A	acceptor_loss	0.9400

AlphaMissense

1878 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:172506519:A:C	S273R	0.999
3:172506519:A:T	S273R	0.999
3:172506521:T:G	S273R	0.999
3:172506673:A:G	L222S	0.999
3:172506876:C:A	W154C	0.999
3:172506876:C:G	W154C	0.999
3:172506878:A:G	W154R	0.999
3:172506878:A:T	W154R	0.999
3:172506565:A:T	V258D	0.998
3:172506589:A:G	L250P	0.998
3:172506778:T:G	Q187P	0.998
3:172506782:A:G	S186P	0.998
3:172506817:A:G	L174P	0.998
3:172509264:G:T	A124D	0.998
3:172506512:C:A	G276W	0.997
3:172506563:A:G	S259P	0.997
3:172506605:C:A	G245W	0.997
3:172506666:T:A	K224N	0.997
3:172506666:T:G	K224N	0.997
3:172506504:A:C	F278L	0.996
3:172506504:A:T	F278L	0.996
3:172506506:A:G	F278L	0.996
3:172506511:C:T	G276E	0.996
3:172506516:A:C	F274L	0.996
3:172506516:A:T	F274L	0.996
3:172506518:A:G	F274L	0.996
3:172506768:A:C	F190L	0.996
3:172506768:A:T	F190L	0.996
3:172506770:A:G	F190L	0.996
3:172506794:A:C	Y182D	0.996

dbSNP variants (sampled 300 via entrez): RS1000042287 (3:172515667 C>T), RS1000074747 (3:172505606 T>A), RS1000110807 (3:172516105 A>T), RS1000176735 (3:172524376 C>T), RS1000437116 (3:172518678 C>G,T), RS1000494960 (3:172524328 ATTTC>A), RS1000560549 (3:172512158 A>G), RS1000591714 (3:172511874 A>T), RS1001174822 (3:172506549 C>T), RS1001427891 (3:172511866 A>C,G), RS1001616021 (3:172518103 C>G,T), RS1001655975 (3:172505365 G>T), RS1001676925 (3:172524227 G>A), RS1001786360 (3:172512786 A>G), RS1001891326 (3:172506979 G>A,T)

Disease associations

OMIM: gene MIM:603598 | disease phenotypes: MIM:227810

GenCC curated gene-disease

Mondo (1): glycogen storage disease due to GLUT2 deficiency (MONDO:0009216)

Orphanet (1): Fanconi-Bickel syndrome (Orphanet:2088)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST003780_2	Breast cancer (estrogen-receptor negative)	2.000000e-08
GCST003782_1	Breast cancer	2.000000e-06
GCST004162_6	Carotid plaque burden	8.000000e-06
GCST004424_18	TRAIL levels	9.000000e-25
GCST004609_118	Monocyte percentage of white cells	5.000000e-09
GCST006613_132	Triglycerides	2.000000e-12
GCST008163_478	Height	1.000000e-06
GCST008399_12	Cocaine dependence	5.000000e-06
GCST010244_269	Triglyceride levels	7.000000e-17
GCST012227_1010	Hip circumference adjusted for BMI	6.000000e-09
GCST90011898_157	Alanine aminotransferase levels	5.000000e-16
GCST90011899_195	Aspartate aminotransferase levels	2.000000e-20
GCST90013663_77	Alanine aminotransferase levels	2.000000e-33
GCST90013664_73	Aspartate aminotransferase levels	7.000000e-30
GCST90016666_12	Liver volume	8.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006501	carotid plaque build
EFO:0008300	TNF-related apoptosis-inducing ligand measurement
EFO:0007989	monocyte percentage of leukocytes
EFO:0004530	triglyceride measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5813 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12488654	TNFSF10		0.00	0

Binding affinities (BindingDB)

1 measured of 9 human assays (9 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
2-(dichloromethyl)-4-(methylthio)-6-(4-nitrophenyl)-1,3,5-triazine	IC50	683 nM

ChEMBL bioactivities

6 potent at pChembl≥5 of 6 total, top 6 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.43	IC50	372	nM	CHEMBL1411210
6.22	IC50	602	nM	CHEMBL1411210
6.17	IC50	683	nM	CHEMBL1570732
6.09	IC50	806	nM	CHEMBL1570732
5.49	IC50	3270	nM	CHEMBL1411210
5.32	IC50	4810	nM	CHEMBL1411210

CTD chemical–gene interactions

291 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Bortezomib	affects cotreatment, decreases reaction, increases activity, increases cleavage, affects reaction (+6 more)	14
Cisplatin	affects expression, increases cleavage, increases response to substance, increases expression, affects response to substance (+6 more)	12
Quercetin	affects cotreatment, decreases reaction, affects reaction, increases expression, increases activity (+5 more)	12
Arsenic Trioxide	increases expression, increases cleavage, decreases expression, increases response to substance, affects cotreatment (+4 more)	9
Cyclosporine	affects cotreatment, decreases reaction, increases expression, decreases expression, decreases response to substance	8
sodium arsenite	affects localization, decreases expression, decreases reaction, increases expression, increases response to substance (+3 more)	7
benzyloxycarbonyl-valyl-alanyl-aspartic acid	increases activity, increases cleavage, increases reaction, affects localization, decreases expression (+4 more)	7
Acetylcysteine	decreases reaction, decreases expression, decreases response to substance, affects cotreatment, increases cleavage (+6 more)	7
Tretinoin	decreases reaction, increases activity, increases expression, increases reaction	7
Resveratrol	decreases expression, increases activity, increases expression, increases reaction, increases response to substance (+5 more)	6
Vorinostat	decreases reaction, decreases activity, decreases phosphorylation, increases cleavage, increases response to substance (+6 more)	6
Estradiol	affects cotreatment, decreases expression, increases expression	6
Fluorouracil	increases activity, increases response to substance, affects cotreatment, increases cleavage, increases reaction (+5 more)	6
perfluorooctanoic acid	decreases expression, increases expression	5
Arsenic	decreases expression, increases expression, increases methylation, increases abundance, affects methylation (+1 more)	5
bisphenol A	affects expression, increases expression, affects cotreatment	4
perfluorooctane sulfonic acid	decreases expression, increases expression	4
Decitabine	increases activity, increases cleavage, decreases reaction, increases expression, affects cotreatment (+2 more)	4
Air Pollutants	decreases expression, increases abundance	4
Cadmium	decreases expression, increases abundance, affects cotreatment, increases expression	4
Curcumin	increases reaction, decreases reaction, increases expression, decreases expression, decreases activity	4
Plant Extracts	decreases response to substance, decreases reaction, increases expression, affects localization, decreases expression (+2 more)	4
Tetrachlorodibenzodioxin	decreases reaction, affects cotreatment, increases expression, affects expression, decreases expression	4
Cadmium Chloride	decreases expression, increases abundance, affects cotreatment	4
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects cotreatment, increases activity, increases expression, increases reaction, increases cleavage	3
SB 203580	increases response to substance, decreases reaction, increases cleavage, increases reaction, affects cotreatment	3
benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone	decreases response to substance, decreases reaction, increases response to substance, decreases activity, affects cotreatment	3
benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone	affects cotreatment, decreases reaction, increases response to substance, decreases activity, decreases response to substance	3
pyrazolanthrone	affects cotreatment, decreases reaction, increases cleavage, increases expression, increases response to substance	3
(+)-JQ1 compound	affects cotreatment, decreases response to substance, increases cleavage, increases reaction, decreases expression	3

ChEMBL screening assays

3 unique, capped per target: 2 functional, 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1000316	Binding	Inhibition of recombinant TRAIL-mediated death of human Jurkat T cells upto 20 uM after 30 mins by 51Cr release assay	Dihydrofuro[3,4-c]pyridinones as inhibitors of the cytolytic effects of the pore-forming glycoprotein perforin. — J Med Chem
CHEMBL1613790	Functional	PUBCHEM_BIOASSAY: SAR analysis of compounds that potentiate TRAIL-induced apoptosis in MDA-MB-435 cells. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID1443, AID1447, AID1624, AID1640]	PubChem BioAssay data set

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1I7	Abcam A-549 TNFSF10 KO	Cancer cell line	Male
CVCL_B2J5	Abcam HeLa TNFSF10 KO	Cancer cell line	Female
CVCL_E0RQ	Ubigene HeLa TNFSF10 KO	Cancer cell line	Female

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT07459582	Not specified	RECRUITING	Accuracy of Home Lactate Meter and Accu-chek Glucometer in Patients With Glycogen Storage Disease