TRADD

Summary

TRADD (TNFRSF1A associated via death domain, HGNC:12030) is a protein-coding gene on chromosome 16q22.1, encoding Tumor necrosis factor receptor type 1-associated DEATH domain protein (Q15628). Adapter molecule for TNFRSF1A/TNFR1 that specifically associates with the cytoplasmic domain of activated TNFRSF1A/TNFR1 mediating its interaction with FADD.

The protein encoded by this gene is a death domain containing adaptor molecule that interacts with TNFRSF1A/TNFR1 and mediates programmed cell death signaling and NF-kappaB activation. This protein binds adaptor protein TRAF2, reduces the recruitment of inhibitor-of-apoptosis proteins (IAPs) by TRAF2, and thus suppresses TRAF2 mediated apoptosis. This protein can also interact with receptor TNFRSF6/FAS and adaptor protein FADD/MORT1, and is involved in the Fas-induced cell death pathway.

Source: NCBI Gene 8717 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 35 total
• MANE Select transcript: NM_003789

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12030
Approved symbol	TRADD
Name	TNFRSF1A associated via death domain
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	Hs.89862
Ensembl gene	ENSG00000102871
Ensembl biotype	protein_coding
OMIM	603500
Entrez	8717

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000345057, ENST00000486556, ENST00000563348, ENST00000566104, ENST00000566247, ENST00000857835, ENST00000857836, ENST00000857837, ENST00000857838, ENST00000959440, ENST00000959441, ENST00000959442

RefSeq mRNA: 2 — MANE Select: NM_003789 NM_001323552, NM_003789

CCDS: CCDS10829

Canonical transcript exons

ENST00000345057 — 5 exons

Exon	Start	End
ENSE00000688477	67155096	67155294
ENSE00000688478	67155377	67155654
ENSE00001861421	67154185	67154959
ENSE00002591400	67159838	67159909
ENSE00003508954	67156510	67156668

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 98.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.8712 / max 134.7412, expressed in 1766 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157742	12.6821	1765
207916	0.1239	54
157741	0.0652	41

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	98.19	gold quality
granulocyte	CL:0000094	94.29	gold quality
cervix squamous epithelium	UBERON:0006922	93.61	silver quality
tongue squamous epithelium	UBERON:0006919	92.91	gold quality
right uterine tube	UBERON:0001302	92.86	gold quality
lower esophagus mucosa	UBERON:0035834	92.79	gold quality
mucosa of transverse colon	UBERON:0004991	92.41	gold quality
amniotic fluid	UBERON:0000173	92.33	gold quality
parotid gland	UBERON:0001831	92.17	gold quality
blood	UBERON:0000178	92.10	gold quality
palpebral conjunctiva	UBERON:0001812	91.38	gold quality
epithelium of nasopharynx	UBERON:0001951	90.86	gold quality
gingival epithelium	UBERON:0001949	90.79	gold quality
spleen	UBERON:0002106	90.71	gold quality
minor salivary gland	UBERON:0001830	90.63	gold quality
mouth mucosa	UBERON:0003729	90.52	gold quality
right coronary artery	UBERON:0001625	90.27	gold quality
esophagus mucosa	UBERON:0002469	90.19	gold quality
epithelium of bronchus	UBERON:0002031	90.14	gold quality
gingiva	UBERON:0001828	90.09	gold quality
saliva-secreting gland	UBERON:0001044	90.00	gold quality
bronchus	UBERON:0002185	90.00	gold quality
squamous epithelium	UBERON:0006914	89.83	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.82	gold quality
leukocyte	CL:0000738	89.68	gold quality
epithelial cell of pancreas	CL:0000083	89.54	silver quality
nasal cavity epithelium	UBERON:0005384	89.53	gold quality
bronchial epithelial cell	CL:0002328	89.51	gold quality
pylorus	UBERON:0001166	89.43	gold quality
monocyte	CL:0000576	89.41	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, FOXO1, NFKB1, NFKB, REL, RELA

miRNA regulators (miRDB)

18 targeting TRADD, 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-4795-3P	100.00	74.62	4024
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-4761-5P	99.51	66.69	804
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-145-3P	99.33	67.66	764
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-9900	96.06	65.48	557

Literature-anchored findings (GeneRIF, showing 40)

• TRADD contains a nuclear export and import sequence that allows shuttling between the nucleus and the cytoplasm. It induces apoptosis via different mechanisms. (PMID:12045187)
• chemotherapeutic drugs exhibited their cytotoxic effects in part by down-regulating Akt signaling following TRADD expression (PMID:12446787)
• Diphtheria toxins induce apoptosis by activating components of the death receptor pathway in a receptor-independent manner. (PMID:12576460)
• TRADD is involved in the p75(NTR)-mediated antiapoptotic activity of nerve growth factor in breast cancer cells (PMID:12604596)
• TRAD binds with keratin 14 and has a role in susceptibility of keratinocytes to caspase-8-mediated apoptosis (PMID:14660619)
• TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm. (PMID:15761471)
• TRADD employs a Pelle-like surface to interact with its binding partners, either receptor TNFR1 or adaptor FADD. (PMID:16006552)
• PAK4 has a role in TNF-alpha induced cell survival pathyways by facilitating TRADD binding to the TNF Receptor (PMID:16227624)
• TRADD and RIP1 compete for recruitment to the TNFR1 signaling complex and the distinct programs of cell death. (PMID:16611992)
• These findings suggest that EMAP-II sensitises endothelial cells to apoptosis by facilitating TNF-R1 apoptotic signalling via TRADD mobilization. (PMID:17051333)
• The expression of TRADD in peripheral blood mononuclear cells was significantly decreased in SLE patients. (PMID:17235653)
• The structure of TRADD DD was solved by NMR. (PMID:17922260)
• unique interaction of LMP1 with TRADD encodes the transforming phenotype of viral TRADD signaling and masks TRADD’s pro-apoptotic function (PMID:18198944)
• Mutations in the TRADD gene may contribute to the development of different hematological diseases. (PMID:18661484)
• glomerular and tubular expression of TNF-alpha, (TNF receptor-associated death domain protein)TRADD, RIP(receptor-interacting protein) and TRAF-2 (TNF receptor-associated factor-) was significantly up-regulated in Lupus nephritis (PMID:19151112)
• Death domain SXXE/D motifs are phosphorylated, as is required for stable TNFR1-TRADD complex formation and subsequent activation of NF-kappaB in inflamed mucosa. (PMID:21724995)
• NSP 5a3a induces apoptosis in Head and Neck cell line HN30 through p73-DAXX and TRAF2-TRADD. (PMID:22170762)
• rpS3 appears to be recruited to the death-inducing signaling complex (DISC) to induce apoptosis by interacting TRADD in response to extracellular stresses. (PMID:22510408)
• Data indicate that silencing tumor necrosis factor receptor 1 (TNFR1)-associated death domain protein (TRADD) in glioma cells results in decreased NF-kappaB activity, decreased proliferation of cells, and increased sensitivity to temozolomide. (PMID:23908590)
• death domains in several proteins, including TRADD, FADD, RIPK1 and TNFR1, were directly inactivated by NleB, an enteropathogenic Escherichia coli (EPEC) type III secretion system effector known to inhibit host nuclear factor-kappaB (NF-kappaB) signalling (PMID:23955153)
• Data indicate that the ASK1-FoxO3a-TRADD-caspase 8 pathway is present in neural tube defects (NTDs)-affected tissues. (PMID:23982205)
• TRADD gene expression was knocked down by an antisense oligonucleotide. (PMID:24070137)
• structure-based mutations of TNFR-1 (P367A and P368A), TRADD (F266A), and RIP1 (M637A and R638A) disrupted formation of the death domain (DD) complex and prevented stable interactions among those DDs (PMID:24361886)
• we demonstrated that the association between DR6 and TRADD was enhanced upon DQM3 stimulation and TRADD was involved in DR6-induced signaling activation (PMID:24374337)
• Biologic assessment found that NPM-RAR expression impaired TNF-induced signaling through TRADD, blunting TNF-mediated activation of caspase-3 (CASP3) and caspase-8 (CASP8), to ultimately block apoptosis. (PMID:25033841)
• PA induced the apoptosis of HUVECs by initiating the death pathway (TNF-R1/TRADD/caspases 8 pathway), whereas AA enhanced cell survival to protect vascular endothelial cells by activating the survival pathway (TNF-R1/RIP/NF-kappaB 50/NF-kappaB 65). (PMID:25230327)
• domains of calmodulin mediate FADD and TRADD interaction (PMID:25643035)
• MicroRNA-30c-2-3p negatively regulates NF-kappaB signaling and cell cycle progression through downregulation of TRADD and CCNE1 in breast cancer. (PMID:25732226)
• NPM-RAR binding to TRADD selectively inhibits caspase activation, while allowing activation of NFkappaB and JNK (PMID:25791120)
• The release of extracellular vesicles was triggered by TNFA from BEAS-2b cells.TNFA-triggered extracellular vesicles contained TNFR1 and TRADD. (PMID:26475675)
• we found that ORF3 protein downregulates TLR3-mediated NF-kappaB signaling via TRADD and RIP1. Our findings provide a new perspective on the cellular response in HEV infection and expand our understanding of the molecular mechanisms of Hepatitis E virus (HEV) pathogenesis in innate immunity. (PMID:27270888)
• These data for the first time identifies miR-485-5p/TRADD axis in hydrogen sulfide protecting against TNF-alpha-induced neuronal cell apoptosis. (PMID:27562714)
• By reducing the levels of TRADD, wild type CFTR suppresses downstream proinflammatory NFkappaB signaling. (PMID:27960153)
• In conclusion, for the first time, we report that TRADD, TRAF2, RIP1 and TAK1 play a role in the regulating TNF-alpha signalling in human myometrium. These findings are of significance given the central role of TNF-alpha in the processes of human labour and delivery. (PMID:28337828)
• Translocation of TRADD to DSBs into the nucleus contributes to cell survival in response to DNA damage through an activation of NHEJ DNA repair. (PMID:28611389)
• potential biological significance of TRADD mediated inflammatory response in the development of uterine leiomyoma, is reported. (PMID:28698006)
• The TRADD C-terminal death domain comprises two super-secondary structures, an all-helix Greek key motif and a beta-hairpin motif flanked by two alpha helices, which make it unique among all known C-terminal death domain structures. (PMID:28765645)
• SNHG9, delivered by adipocyte-derived exosomes, alleviates inflammation and apoptosis of endothelial cells through suppressing TRADD expression. (PMID:32007500)
• Coronin 1B regulates the TNFalpha-induced apoptosis of HUVECs by mediating the interaction between TRADD and FADD. (PMID:32303335)
• Modulating TRADD to restore cellular homeostasis and inhibit apoptosis. (PMID:32968279)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tradd	ENSDARG00000036057
mus_musculus	Tradd	ENSMUSG00000031887
rattus_norvegicus	Tradd	ENSRNOG00000015179

Protein

Protein identifiers

Tumor necrosis factor receptor type 1-associated DEATH domain protein — Q15628 (reviewed: Q15628)

Alternative names: TNFRSF1A-associated via death domain

All UniProt accessions (1): Q15628

UniProt curated annotations — full annotation on UniProt →

Function. Adapter molecule for TNFRSF1A/TNFR1 that specifically associates with the cytoplasmic domain of activated TNFRSF1A/TNFR1 mediating its interaction with FADD. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa-B. The nuclear form acts as a tumor suppressor by preventing ubiquitination and degradation of isoform p19ARF/ARF of CDKN2A by TRIP12: acts by interacting with TRIP12, leading to disrupt interaction between TRIP12 and isoform p19ARF/ARF of CDKN2A.

Subunit / interactions. Stimulation of TNF receptor TNFRSF1A leads to the formation of two distinct signaling complexes. Plasma membrane-bound complex I is composed of TNFRSF1A, TRADD, RIPK1, TRAF2 and BIRC2/c-IAP1 or BIRC3 which interacts with CHUCK/IKK-alpha, IKBKB/IKK-beta and IKBKG/IKK-gamma promoting cell survival. Subsequently, TRADD, RIPK1 and TRAF2 dissociate from TNFRSF1A and form cytoplasmic complex II with FADD and caspase CASP8 promoting cell apoptosis. Within complex I, interacts with TNFRSF1A/TNFR1, TRAF2 and kinase RIPK1. Within complex I, interacts with TRPC4AP; the interaction promotes NF-kappa B activation. UXT1 associates with complex I; the interaction prevents the formation of complex II. Within complex I Interacts with scaffold protein DAB2IP. Interacts with autophagy receptor SQSTM1. Interacts with E3 ligase TRIP12. Interacts with kinase HIPK2. Interacts with keratin KRT14. Interacts with keratin KRT18. Interacts with keratins KRT16 and KRT17. Interacts with FADD. Interacts with TOMM70. Interacts with TMC8; the interaction impairs the formation of complex I and facilites complex II formation.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton.

Tissue specificity. Found in all examined tissues.

Post-translational modifications. (Microbial infection) Glycosylated at Arg-235 by enteropathogenic E.coli protein NleB1, C.rodentium protein NleB and S.typhimurium proteins Ssek1 and Ssek3: arginine GlcNAcylation prevents homotypic/heterotypic death domain interactions and assembly of the oligomeric TNFRSF1A/TNFR1 complex, thereby disrupting TNF signaling.

Domain organisation. Requires the intact death domain to associate with TNFRSF1A/TNFR1.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15628-1	1	yes
Q15628-2	2

RefSeq proteins (2): NP_001310481, NP_003780* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000488	Death_dom	Domain
IPR009095	TRADD_N	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR035712	TRADD	Family
IPR036729	TRADD_N_sf	Homologous_superfamily

Pfam: PF00531, PF09034

UniProt features (38 total): helix 17, strand 7, mutagenesis site 2, turn 2, region of interest 2, short sequence motif 2, glycosylation site 2, chain 1, domain 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6AC0	X-RAY DIFFRACTION	1.45
1F3V	X-RAY DIFFRACTION	2
9VGD	ELECTRON MICROSCOPY	3.3
9VIN	ELECTRON MICROSCOPY	3.41
1F2H	SOLUTION NMR
5XME	SOLUTION NMR
7CSQ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15628-F1	84.45	0.62

Functional residue map

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

Glycosylation sites (2): 235, 245

Mutagenesis-validated functional residues (2):

Position	Phenotype
235	abolished glcnacylation by e.coli nleb1. abolished ability to self-oligomerize. strongly reduced glcnacylation by s.typh
245	strongly reduced glcnacylation by s.typhimurium ssek1; when associated with a-235.

Function

Pathways and Gene Ontology

Reactome pathways

11 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-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway
R-HSA-5675482	Regulation of necroptotic cell death
R-HSA-69416	Dimerization of procaspase-8
R-HSA-75893	TNF signaling
R-HSA-9693928	Defective RIPK1-mediated regulated necrosis

MSigDB gene sets: 255 (showing top): BIOCARTA_RELA_PATHWAY, GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, chr16q22, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_REGULATION_OF_HAIR_CYCLE, GOBP_REGULATION_OF_HAIR_FOLLICLE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, SMITH_TERT_TARGETS_DN

GO Biological Process (19): protein polyubiquitination (GO:0000209), apoptotic process (GO:0006915), signal transduction (GO:0007165), canonical NF-kappaB signal transduction (GO:0007249), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), positive regulation of cell migration (GO:0030335), positive regulation of interferon-beta production (GO:0032728), tumor necrosis factor-mediated signaling pathway (GO:0033209), TRAIL-activated apoptotic signaling pathway (GO:0036462), positive regulation of apoptotic process (GO:0043065), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), positive regulation of inflammatory response (GO:0050729), positive regulation of hair follicle development (GO:0051798), cellular response to tumor necrosis factor (GO:0071356), extrinsic apoptotic signaling pathway (GO:0097191), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), non-canonical NF-kappaB signal transduction (GO:0038061), apoptotic signaling pathway (GO:0097190)

GO Molecular Function (8): transmembrane receptor protein tyrosine kinase adaptor activity (GO:0005068), kinase binding (GO:0019900), protein-macromolecule adaptor activity (GO:0030674), signaling adaptor activity (GO:0035591), identical protein binding (GO:0042802), death domain binding (GO:0070513), protein binding (GO:0005515), molecular adaptor activity (GO:0060090)

GO Cellular Component (9): tumor necrosis factor receptor superfamily complex (GO:0002947), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), death-inducing signaling complex (GO:0031264), signaling receptor complex (GO:0043235)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
TNF signaling	3
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
RIPK1-mediated regulated necrosis	1
Death Receptor Signaling	1
Diseases of programmed cell death	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic signaling pathway	2
intracellular signaling cassette	2
apoptotic process	2
canonical NF-kappaB signal transduction	2
regulation of canonical NF-kappaB signal transduction	2
protein binding	2
binding	2
cellular anatomical structure	2
protein ubiquitination	1
programmed cell death	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
extrinsic apoptotic signaling pathway	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
positive regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
extrinsic apoptotic signaling pathway via death domain receptors	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
positive regulation of intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
hair follicle development	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
regulation of hair follicle development	1
response to tumor necrosis factor	1
cellular response to cytokine stimulus	1

Protein interactions and networks

STRING

1806 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRADD	TNFRSF1A	P19438	999
TRADD	FADD	Q13158	999
TRADD	RIPK1	Q13546	998
TRADD	CASP8	Q14790	997
TRADD	RIPK3	Q9Y572	996
TRADD	TRAF2	Q12933	996
TRADD	TRAF5	O00463	996
TRADD	TNF	P01375	996
TRADD	BIRC2	Q13490	996
TRADD	TRAF1	Q13077	994
TRADD	TRAF3	Q13114	994
TRADD	BIRC3	Q13489	993
TRADD	CFLAR	O15519	992
TRADD	CYLD	Q9NQC7	991
TRADD	TANK	Q92844	990

IntAct

143 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
TNFRSF1A	TRADD	psi-mi:“MI:0915”(physical association)	0.960
TNFRSF1A	TRADD	psi-mi:“MI:0914”(association)	0.960
TNF	TNFRSF1A	psi-mi:“MI:0914”(association)	0.960
TRADD	TNFRSF1A	psi-mi:“MI:0915”(physical association)	0.960
CASP8	RIPK1	psi-mi:“MI:0914”(association)	0.960
TNFRSF1A	TRADD	psi-mi:“MI:0407”(direct interaction)	0.960
TRAF2	TRADD	psi-mi:“MI:0407”(direct interaction)	0.940
KRT18	KRT8	psi-mi:“MI:0915”(physical association)	0.940
KRT18	KRT8	psi-mi:“MI:0403”(colocalization)	0.940
TRADD	TRAF2	psi-mi:“MI:0915”(physical association)	0.940
TRAF2	TRADD	psi-mi:“MI:0915”(physical association)	0.940
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
TNFRSF1A	RIPK1	psi-mi:“MI:0914”(association)	0.880
TNF	TRAF2	psi-mi:“MI:0914”(association)	0.840
FADD	TRADD	psi-mi:“MI:0915”(physical association)	0.810

BioGRID (221): IFIT3 (Affinity Capture-Western), TRADD (Affinity Capture-Western), TRADD (Affinity Capture-MS), TRADD (Affinity Capture-MS), TRADD (Affinity Capture-MS), TRADD (Affinity Capture-Western), TRAF6 (Affinity Capture-Western), TRADD (Affinity Capture-Western), TRADD (Affinity Capture-Western), TRADD (Affinity Capture-MS), TRADD (Affinity Capture-MS), TRADD (Affinity Capture-MS), TRADD (Affinity Capture-Western), TRADD (Affinity Capture-Western), TRADD (Affinity Capture-Western)

ESM2 similar proteins: A3KN95, A4IFG4, A7E2I7, E2RDP2, J3QMI4, O94810, O95382, P0C5W1, P23677, P82350, Q15628, Q16586, Q1RMX3, Q24JP5, Q28686, Q29RH2, Q3T904, Q3U0S6, Q45T69, Q49LS1, Q5FWU3, Q5RCS0, Q5U651, Q64255, Q674R7, Q684M2, Q68FE2, Q68FE7, Q6EBV9, Q6GQT5, Q6NY19, Q6P9Q4, Q6PEY1, Q7Z3C6, Q80WF4, Q80XF7, Q86TL0, Q86XJ0, Q8C052, Q8C152

Diamond homologs: Q15628, Q1M161, Q2KI74, Q32NG6, Q3U0V2, Q9I9N5, Q13546, Q60855, Q8R3N6, Q96FV9

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
TNFRSF21	up-regulates	TRADD	binding
TNFRSF25	up-regulates	TRADD	binding
TNFRSF1A	“up-regulates activity”	TRADD	binding
TRADD	“up-regulates activity”	CASP8	binding
TRADD	“up-regulates activity”	FADD	binding
TRADD	up-regulates	TRAF5	binding
KRT14	“down-regulates activity”	TRADD	binding
TRADD	“up-regulates activity”	RIPK1	binding
TRADD	“up-regulates activity”	TRAF2	binding
TRADD	“up-regulates activity”	BIRC2	binding
TRADD	up-regulates	TRAF1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of NF-kappa B signaling	6	64.5×	3e-08
TNFR1-induced NF-kappa-B signaling pathway	11	62.6×	3e-15
TICAM1, RIP1-mediated IKK complex recruitment	6	61.1×	3e-08
TNFR1-induced proapoptotic signaling	8	59.6×	1e-10
Regulation of TNFR1 signaling	14	53.1×	2e-18
Regulation of necroptotic cell death	7	52.1×	6e-09
IKK complex recruitment mediated by RIP1	6	50.5×	7e-08
TNF signaling	7	50.2×	7e-09

GO biological processes:

GO term	Partners	Fold	FDR
tumor necrosis factor-mediated signaling pathway	11	51.9×	1e-13
canonical NF-kappaB signal transduction	8	41.9×	6e-09
extrinsic apoptotic signaling pathway via death domain receptors	5	28.7×	6e-05
extrinsic apoptotic signaling pathway	6	26.3×	1e-05
response to unfolded protein	6	25.8×	1e-05
negative regulation of canonical NF-kappaB signal transduction	9	22.1×	8e-08
obsolete positive regulation of NF-kappaB transcription factor activity	7	20.6×	7e-06
positive regulation of neuron apoptotic process	5	19.4×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1306 predictions. Top by Δscore:

Variant	Effect	Δscore
16:67154955:ATTCA:A	acceptor_gain	1.0000
16:67154956:TTCA:T	acceptor_gain	1.0000
16:67154957:TCA:T	acceptor_gain	1.0000
16:67154958:CA:C	acceptor_gain	1.0000
16:67154958:CAC:C	acceptor_gain	1.0000
16:67154959:ACT:A	acceptor_loss	1.0000
16:67154960:C:CC	acceptor_gain	1.0000
16:67154960:CTG:C	acceptor_loss	1.0000
16:67154963:C:CT	acceptor_gain	1.0000
16:67155099:CAGG:C	donor_gain	1.0000
16:67155237:T:TA	donor_gain	1.0000
16:67155291:CGGG:C	acceptor_gain	1.0000
16:67155295:C:CC	acceptor_gain	1.0000
16:67155375:A:T	donor_loss	1.0000
16:67155376:C:CA	donor_loss	1.0000
16:67155376:CCTG:C	donor_gain	1.0000
16:67161733:A:AG	acceptor_gain	1.0000
16:67161734:G:GG	acceptor_gain	1.0000
16:67161734:GGCC:G	acceptor_gain	1.0000
16:67161934:TCAGG:T	donor_loss	1.0000
16:67161935:CAGG:C	donor_loss	1.0000
16:67161936:AGGTG:A	donor_loss	1.0000
16:67161937:GGTG:G	donor_loss	1.0000
16:67161938:GT:G	donor_loss	1.0000
16:67161939:T:A	donor_loss	1.0000
16:67162834:G:A	acceptor_gain	1.0000
16:67162840:A:AG	acceptor_gain	1.0000
16:67154964:A:T	acceptor_gain	0.9900
16:67155098:A:AC	donor_gain	0.9900
16:67155099:C:CC	donor_gain	0.9900

AlphaMissense

1956 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:67154898:C:A	W230C	0.999
16:67154898:C:G	W230C	0.999
16:67154900:A:G	W230R	0.999
16:67154900:A:T	W230R	0.999
16:67154722:A:T	L289H	0.998
16:67154923:A:G	F222S	0.998
16:67154772:G:C	F272L	0.996
16:67154772:G:T	F272L	0.996
16:67154774:A:G	F272L	0.996
16:67154922:G:C	F222L	0.996
16:67154922:G:T	F222L	0.996
16:67154923:A:C	F222C	0.996
16:67154924:A:G	F222L	0.996
16:67154773:A:G	F272S	0.995
16:67154722:A:G	L289P	0.994
16:67154734:A:G	L285P	0.994
16:67154785:A:G	L268P	0.994
16:67155118:A:C	F202L	0.994
16:67155118:A:T	F202L	0.994
16:67155120:A:G	F202L	0.994
16:67154707:A:G	L294P	0.993
16:67154749:G:T	A280D	0.993
16:67154897:G:T	R231S	0.993
16:67154887:C:T	G234E	0.992
16:67154920:G:T	A223E	0.992
16:67154790:G:C	F266L	0.991
16:67154790:G:T	F266L	0.991
16:67154792:A:G	F266L	0.991
16:67154796:C:A	Q264H	0.991
16:67154796:C:G	Q264H	0.991

dbSNP variants (sampled 300 via entrez): RS1000134243 (16:67157605 A>C), RS1000270435 (16:67157283 C>T), RS1000371785 (16:67155968 C>T), RS1000879920 (16:67161279 A>G), RS1001230278 (16:67161479 G>A), RS1001352678 (16:67157095 T>G), RS1002167686 (16:67154863 C>A,G,T), RS1002389252 (16:67161889 G>A,C), RS1002829272 (16:67157982 G>T), RS1003165103 (16:67155187 G>A), RS1003170681 (16:67156254 G>A), RS1003438615 (16:67155471 A>G), RS1003909948 (16:67153824 C>A), RS1004341016 (16:67154836 G>A), RS1004466549 (16:67161238 C>G,T)

Disease associations

OMIM: gene MIM:603500 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases reaction, affects cotreatment, affects expression	6
dioscin	increases expression	2
Cisplatin	increases expression, decreases response to substance, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Plant Extracts	increases expression, affects cotreatment	2
Tetrachlorodibenzodioxin	increases expression	2
Magnetite Nanoparticles	affects cotreatment, increases expression, decreases expression	2
bisphenol F	affects cotreatment, decreases expression	1
moringin	affects cotreatment, decreases expression	1
picrasidine I	decreases expression	1
parthenolide	increases expression	1
2-anisidine	decreases expression	1
triphenyl phosphate	affects expression	1
propylparaben	increases expression	1
sodium arsenate	affects expression, increases abundance	1
VX-agent	increases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
trichostatin A	affects cotreatment, increases expression	1
sodium arsenite	increases expression	1
rhein	increases expression	1
ferrous sulfate	decreases expression	1
saikosaponin D	increases expression	1
beta-solamarine	increases expression	1
coumarin	increases expression	1
hydroquinone	increases expression	1
1’-acetoxychavicol acetate	decreases reaction, increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
anacardic acid	decreases activity	1
cylindrospermopsin	increases expression	1

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8A2	Abcam Raji TRADD KO	Cancer cell line	Male
CVCL_C0AW	Abcam THP-1 TRADD KO	Cancer cell line	Male
CVCL_C7CJ	Abcam PC-3 TRADD KO	Cancer cell line	Male
CVCL_D8CW	Ubigene A-549 TRADD KO	Cancer cell line	Male
CVCL_D8XJ	Ubigene HCT 116 TRADD KO	Cancer cell line	Male
CVCL_D9US	Ubigene HEK293 TRADD KO	Transformed cell line	Female
CVCL_E0RY	Ubigene HeLa TRADD KO	Cancer cell line	Female

Clinical trials (associated diseases)

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