TNFRSF1B

Summary

TNFRSF1B (TNF receptor superfamily member 1B, HGNC:11917) is a protein-coding gene on chromosome 1p36.22, encoding Tumor necrosis factor receptor superfamily member 1B (P20333). Receptor with high affinity for TNFSF2/TNF and approximately 5-fold lower affinity for homotrimeric TNFSF1/lymphotoxin-alpha.

The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein and TNF-receptor 1 form a heterocomplex that mediates the recruitment of two anti-apoptotic proteins, c-IAP1 and c-IAP2, which possess E3 ubiquitin ligase activity. The function of IAPs in TNF-receptor signalling is unknown, however, c-IAP1 is thought to potentiate TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2, which mediates anti-apoptotic signals. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways.

Source: NCBI Gene 7133 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 62 total
• Phenotypes (HPO): 45
• Druggable target: yes
• MANE Select transcript: NM_001066

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11917
Approved symbol	TNFRSF1B
Name	TNF receptor superfamily member 1B
Location	1p36.22
Locus type	gene with protein product
Status	Approved
Aliases	TNFBR, TNFR80, TNF-R75, TNF-R-II, p75, CD120b
Ensembl gene	ENSG00000028137
Ensembl biotype	protein_coding
OMIM	191191
Entrez	7133

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000376259, ENST00000489921, ENST00000492361, ENST00000536782, ENST00000857300, ENST00000857301, ENST00000857302, ENST00000857303, ENST00000857304, ENST00000941754, ENST00000941755, ENST00000941756, ENST00000941757, ENST00000941758

RefSeq mRNA: 1 — MANE Select: NM_001066 NM_001066

CCDS: CCDS145

Canonical transcript exons

ENST00000376259 — 10 exons

Exon	Start	End
ENSE00001043020	12188796	12188895
ENSE00003463481	12192863	12193098
ENSE00003489506	12193955	12194032
ENSE00003511838	12190957	12191085
ENSE00003553008	12191774	12191923
ENSE00003573413	12192431	12192524
ENSE00003573986	12201967	12202171
ENSE00003591048	12206740	12209220
ENSE00003628593	12194584	12194618
ENSE00003851114	12166991	12167169

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 98.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 114.0785 / max 6478.9329, expressed in 1416 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
710	113.2002	1416
717	0.4759	176
718	0.4025	164

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.99	gold quality
monocyte	CL:0000576	98.94	gold quality
leukocyte	CL:0000738	98.88	gold quality
mononuclear cell	CL:0000842	98.86	gold quality
blood	UBERON:0000178	98.56	gold quality
spleen	UBERON:0002106	95.97	gold quality
vermiform appendix	UBERON:0001154	94.94	gold quality
tendon of biceps brachii	UBERON:0008188	93.54	gold quality
right lung	UBERON:0002167	93.39	gold quality
omental fat pad	UBERON:0010414	93.36	gold quality
peritoneum	UBERON:0002358	93.32	gold quality
lymph node	UBERON:0000029	93.16	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.11	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.47	gold quality
periodontal ligament	UBERON:0008266	92.22	gold quality
caecum	UBERON:0001153	92.08	gold quality
upper lobe of left lung	UBERON:0008952	91.64	gold quality
pericardium	UBERON:0002407	91.26	gold quality
adipose tissue	UBERON:0001013	91.23	gold quality
connective tissue	UBERON:0002384	90.86	gold quality
gall bladder	UBERON:0002110	90.82	gold quality
apex of heart	UBERON:0002098	90.69	gold quality
upper lobe of lung	UBERON:0008948	90.49	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.58	gold quality
middle frontal gyrus	UBERON:0002702	89.48	gold quality
bone marrow cell	CL:0002092	89.36	gold quality
bone marrow	UBERON:0002371	89.24	gold quality
small intestine	UBERON:0002108	88.38	gold quality
tibial nerve	UBERON:0001323	88.34	gold quality
cartilage tissue	UBERON:0002418	88.10	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-CURD-97	yes	1395.24
E-CURD-55	yes	879.06
E-CURD-89	yes	443.79
E-CURD-122	yes	72.09
E-GEOD-84465	yes	39.82
E-MTAB-8142	yes	39.77
E-HCAD-10	yes	39.46
E-MTAB-9221	yes	27.31
E-MTAB-6678	yes	23.64
E-CURD-112	yes	17.99
E-MTAB-9067	yes	11.16
E-CURD-119	yes	4.52
E-CURD-120	no	30.74
E-MTAB-5061	no	3.66
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, CUX1, EGR1, FOXC1, FOXO3, HAND1, HAND2, IRF6, JUN, MITF, NFKB, SP1, STAT3, TCF12, TCF3

miRNA regulators (miRDB)

79 targeting TNFRSF1B, 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-8485	100.00	77.57	4731
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-1184	99.99	68.19	1458
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838

Literature-anchored findings (GeneRIF, showing 40)

• induced marked apoptosis in T cells from HIV-infected persons; associated with both alteration of Bcl-2 expression and activation of caspase-8 and caspase-3 (PMID:11861282)
• insulin resistance and blood pressure are linked to altered shedding of TNF-alpha receptors in type 2 diabetes mellitus (PMID:11882518)
• Polymorphisms of the TNF gene and the TNF receptor superfamily member 1B gene are associated with susceptibility to ulcerative colitis and Crohn’s disease, respectively. (PMID:11904678)
• mediates ubiquitination and degradation of TRAF2 (PMID:11907583)
• TNFRII exon 6 SNP does not seem to be associated with susceptibility to juvenile idiopathic arthritis. (PMID:11961180)
• polymorphism is associated with the incidence of graft-versus-host disease and relapse rate in unrelated bone marrow transplantation (uBMT) (PMID:11979305)
• a possible marker for the early diagnosis of rejection and for prognosis after renal transplantation (PMID:12122509)
• The high level of TNF alpha expression was noted both for typical and sought TNF R2/R7 isoforms and 3) A considerable number of samples displayed higher levels of TNF R2 isoforms than TNF R2/R7 mRNA expression in differentiated thyroid carcinomas (PMID:12144133)
• methionine 196 arginine polymorphism in exon 6 of the TNF receptor 2 gene (TNFRSF1B) is associated with the polycystic ovary syndrome and hyperandrogenism. (PMID:12161545)
• A TNFR2 recessive factor, in linkage disequilibrium with the 196R allele, plays a major role in a subset of families with multiple cases of rheumatoid arthritis. (PMID:12209506)
• Review. Blockade of the p75TNFR may be helpful in treating systemic autoimmunity since its function may be essential for systemic tissue damage. (PMID:12220546)
• in patients with rheumatoid arthritis, preliminary study results showed a trend towards a higher prevalence of the GG genotype for the exon 6 TNFRII polymorphism in the less responsive patients with more aggressive disease (PMID:12233877)
• Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells, suggesting a possible role for TNF-mediated events during co-stimulation. (PMID:12296856)
• Increased levels of this receptor are found in lean nondiabetic offspring of type 2 diabetic subjects. (PMID:12351485)
• Both adipose tissue and blood PAI-1 levels were positively associated with TNFRSF1A and TNFRSF1B in obesity. (PMID:12353079)
• plasma IL-8 was related to body mass index, percentage of body fat, fat mass and soluble TNF-alpha receptor 2 (PMID:12364441)
• TNFR2 binds to Etk but is not involved in Etk activation in human cells (PMID:12370298)
• Review: role in signaling in chronic inflammatory disorders (PMID:12371624)
• Elevated serum levels of soluble TNF-alpha receptor type II are strongly associated with the development of acute renal failure in patients with septic shock. (PMID:12500222)
• serum levels elevated in asthmatic patients during acute attack (PMID:12530121)
• No association with narcolepsy in German patients, in contrast with Japanese. (PMID:12601524)
• Plasma sTNFR1 and sTNFR2 were inversely related to insulin sensitivity and might contribute to the development of insulin resistance in glucose-intolerant subjects. (PMID:12610052)
• TNFR2ms 18 may have a protective effect on the development of rheumatoid arthritis in Taiwanese, while TNFR2ms 15 tends to have a precipitating effect. (PMID:12610797)
• An ethnic difference in the TNFR2 promoter variable number of tandem repeats has been found that may be associated with clinical phenotypes in systemic lupus erythematosus. (PMID:12739039)
• TNFR2 activates cytosolic phospholipase A2 (cPLA2) by causing its translocation to plasma membrane and perinuclear subcellular regions and by causing an increase in intracellular calcium that may contribute to the translocation and activation of cPLA2. (PMID:12786601)
• Neither the +36 TNFRSF1A SNP nor the +196 TNFRSF1B SNP is associated with RA severity in a population of Caucasian patients with rheumatoid arthritis. (PMID:12858434)
• levels of sTNFR concentrations were either similar (in sera) or significantly lower (in CM) in the patients with acute HPV infection compared with the controls (PMID:12880679)
• TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis (PMID:12882979)
• Serum levels and Adamantiades-Behcet’s disease activity (PMID:12918703)
• TNF-RII plays a unique role among the T cell costimulatory molecules, as TNF-RII ligation can have positive and negative effects on TCR-dependent signaling. (PMID:12960285)
• Deficient expression of TNF-RII mRNA in the endometrium of women at the earliest stages of endometriosis may play a significant role in the pathophysiology of this disease. (PMID:14506926)
• cells pre-stimulated through TNFR-2 prior to subsequent activation of TNFR-1, showed enhanced cell death and recruitment of RIP to the TNFR-1 complex; TNFR-2 signaling may play a role in controlling viral infection (PMID:14532286)
• There is a significant association between exon 10 nt 1668*T–>G tumor necrosis factor receptor 2 gene polymorphism of and susceptibility to MS. (PMID:14651520)
• Association between recipient and donor TNFRII 196R allele status and acute or extensive chronic GVHD incidence, respectively, may reflect reduced circulating sTNFRII. (PMID:14688526)
• The level of the sTNF-R2 was elevated in myelodysplastic syndrome(MDS) patients. (PMID:14728878)
• Distribution of the TNFR2 196 R/R and TNFR1 +36 A/A genotypes in familial rheumatoid arthritis could suggest an interaction between TNFR1 and TNFR2 in the genetic susceptibility for rheumatoid arthritis. (PMID:14872483)
• significantly up-regulated in plasma of HIV seropositive patients who used opiates compared to those who did not. (PMID:15000697)
• Association between the TNFRII 196 M/R gene polymorphism and the functional severity of early rheumatoid arthritis. (PMID:15022314)
• Expression of TNF-receptor 2 (TNF-R2) but not TNF-receptor 1 (TNF-R1) was detected in myeloma cell lines. (PMID:15041705)
• The TNFRII 196R G allele does not appear to be associated with Alzheimer’s disease susceptibility in a Japanese population. (PMID:15091317)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cd40	ENSDARG00000054968
danio_rerio	tnfrsf1b	ENSDARG00000070165
danio_rerio	tnfrsf11a	ENSDARG00000087804
mus_musculus	Tnfrsf1b	ENSMUSG00000028599
rattus_norvegicus	Tnfrsf1b	ENSRNOG00000016575

Paralogs (21): FAS (ENSG00000026103), TNFRSF9 (ENSG00000049249), RELT (ENSG00000054967), NGFR (ENSG00000064300), TNFRSF1A (ENSG00000067182), CD40 (ENSG00000101017), TNFRSF10A (ENSG00000104689), LTBR (ENSG00000111321), TNFRSF10B (ENSG00000120889), TNFRSF8 (ENSG00000120949), CD27 (ENSG00000139193), TNFRSF11A (ENSG00000141655), TNFRSF21 (ENSG00000146072), TNFRSF14 (ENSG00000157873), TNFRSF11B (ENSG00000164761), TNFRSF10D (ENSG00000173530), TNFRSF10C (ENSG00000173535), TNFRSF4 (ENSG00000186827), TNFRSF18 (ENSG00000186891), TNFRSF25 (ENSG00000215788), TNFRSF6B (ENSG00000243509)

Protein

Protein identifiers

Tumor necrosis factor receptor superfamily member 1B — P20333 (reviewed: P20333)

Alternative names: Tumor necrosis factor receptor 2, Tumor necrosis factor receptor type II, p75, p80 TNF-alpha receptor

All UniProt accessions (2): B5A977, P20333

UniProt curated annotations — full annotation on UniProt →

Function. Receptor with high affinity for TNFSF2/TNF and approximately 5-fold lower affinity for homotrimeric TNFSF1/lymphotoxin-alpha. The TRAF1/TRAF2 complex recruits the apoptotic suppressors BIRC2 and BIRC3 to TNFRSF1B/TNFR2. This receptor mediates most of the metabolic effects of TNF. Isoform 2 blocks TNF-induced apoptosis, which suggests that it regulates TNF function by antagonizing its biological activity.

Subunit / interactions. Binds to TRAF2. Interacts with BMX. Interacts (activated form) with XPNPEP3.

Subcellular location. Cell membrane Secreted Secreted.

Post-translational modifications. Phosphorylated; mainly on serine residues and with a very low level on threonine residues. A soluble form (tumor necrosis factor binding protein 2) is produced from the membrane form by proteolytic processing.

Isoforms (2)

UniProt ID	Names	Canonical?
P20333-1	1	yes
P20333-2	2, DS-TNFR2(Delta7,8), sTNFR2

RefSeq proteins (1): NP_001057* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001368	TNFR/NGFR_Cys_rich_reg	Domain
IPR020411	TNFR_1B	Family
IPR033996	TNFRSF1B_N	Domain
IPR051670	TNF_chemokine_rcpt-like	Family

Pfam: PF00020

UniProt features (70 total): strand 17, disulfide bond 10, sequence variant 8, compositionally biased region 6, glycosylation site 6, sequence conflict 5, repeat 4, region of interest 3, chain 2, topological domain 2, splice variant 2, turn 2, signal peptide 1, modified residue 1, transmembrane region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9CU8	X-RAY DIFFRACTION	1.96
1CA9	X-RAY DIFFRACTION	2.3
3ALQ	X-RAY DIFFRACTION	3
8HLB	ELECTRON MICROSCOPY	3.63
9LFL	ELECTRON MICROSCOPY	3.73

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20333-F1	67.28	0.40

Antibody-complex structures (SAbDab): 1 — 8HLB

Functional residue map

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

Post-translational modifications (1): 330

Disulfide bonds (10): 40–53, 54–67, 57–75, 78–93, 96–110, 100–118, 120–126, 134–143, 137–161, 164–179

Glycosylation sites (6): 30, 171, 193, 206, 221, 222

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway
R-HSA-5669034	TNFs bind their physiological receptors
R-HSA-6783783	Interleukin-10 signaling
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 663 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, FERRANDO_TAL1_NEIGHBORS, BIOCARTA_TNFR2_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, CREL_01, BIOCARTA_RELA_PATHWAY, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, MCLACHLAN_DENTAL_CARIES_UP, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, BASSO_B_LYMPHOCYTE_NETWORK

GO Biological Process (24): regulation of cytokine production involved in immune response (GO:0002718), regulation of T cell cytokine production (GO:0002724), aortic valve development (GO:0003176), pulmonary valve development (GO:0003177), negative regulation of extracellular matrix constituent secretion (GO:0003332), inflammatory response (GO:0006954), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), negative regulation of cardiac muscle hypertrophy (GO:0010614), regulation of myelination (GO:0031641), positive regulation of myelination (GO:0031643), tumor necrosis factor-mediated signaling pathway (GO:0033209), regulation of T cell proliferation (GO:0042129), positive regulation of oligodendrocyte differentiation (GO:0048714), RNA destabilization (GO:0050779), positive regulation of membrane protein ectodomain proteolysis (GO:0051044), cellular response to lipopolysaccharide (GO:0071222), extrinsic apoptotic signaling pathway (GO:0097191), regulation of neuroinflammatory response (GO:0150077), negative regulation of neuroinflammatory response (GO:0150079), glial cell-neuron signaling (GO:0150098), positive regulation of apoptotic process involved in morphogenesis (GO:1902339), apoptotic process (GO:0006915), cell surface receptor signaling pathway (GO:0007166), negative regulation of inflammatory response (GO:0050728)

GO Molecular Function (4): tumor necrosis factor receptor activity (GO:0005031), ubiquitin protein ligase binding (GO:0031625), tumor necrosis factor binding (GO:0043120), protein binding (GO:0005515)

GO Cellular Component (6): tumor necrosis factor receptor superfamily complex (GO:0002947), extracellular region (GO:0005576), plasma membrane (GO:0005886), membrane (GO:0016020), specific granule membrane (GO:0035579), membrane raft (GO:0045121)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by Interleukins	2
Cytokine Signaling in Immune system	1
TNFR2 non-canonical NF-kB pathway	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
semi-lunar valve development	2
myelination	2
neuroinflammatory response	2
cellular anatomical structure	2
regulation of cytokine production	1
cytokine production involved in immune response	1
regulation of production of molecular mediator of immune response	1
T cell cytokine production	1
regulation of T cell mediated immunity	1
regulation of cytokine production involved in immune response	1
regulation of extracellular matrix constituent secretion	1
extracellular matrix constituent secretion	1
negative regulation of extracellular matrix organization	1
negative regulation of secretion by cell	1
defense response	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
negative regulation of muscle hypertrophy	1
regulation of cellular process	1
regulation of nervous system development	1
regulation of myelination	1
positive regulation of nervous system process	1
positive regulation of cellular process	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
T cell proliferation	1
regulation of lymphocyte proliferation	1
regulation of T cell activation	1
positive regulation of glial cell differentiation	1
oligodendrocyte differentiation	1
regulation of oligodendrocyte differentiation	1
RNA catabolic process	1
positive regulation of catabolic process	1
regulation of RNA stability	1
positive regulation of RNA metabolic process	1
membrane protein ectodomain proteolysis	1
positive regulation of protein catabolic process	1
positive regulation of proteolysis	1

Protein interactions and networks

STRING

2574 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFRSF1B	TNF	P01375	998
TNFRSF1B	LTA	P01374	994
TNFRSF1B	TRAF1	Q13077	989
TNFRSF1B	TNFRSF1A	P19438	988
TNFRSF1B	KRT18	P05783	921
TNFRSF1B	IL1B	P01584	898
TNFRSF1B	IL6	P05231	834
TNFRSF1B	BIRC3	Q13489	822
TNFRSF1B	TRAF3	Q13114	807
TNFRSF1B	IFNG	P01579	792
TNFRSF1B	FASLG	P48023	776
TNFRSF1B	BIRC2	Q13490	766
TNFRSF1B	IL2RA	P01589	758
TNFRSF1B	IL1A	P01583	754
TNFRSF1B	TNFRSF8	P28908	747

IntAct

119 interactions, top by confidence:

A	B	Type	Score
TNF	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.790
TNF	TNFRSF1B	psi-mi:“MI:0407”(direct interaction)	0.790
TNFRSF1B	TNF	psi-mi:“MI:0407”(direct interaction)	0.790
TNFRSF1B	TRAF2	psi-mi:“MI:0915”(physical association)	0.750
TRAF2	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.750
TRAF1	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.660
TNFRSF1B	GRN	psi-mi:“MI:0407”(direct interaction)	0.640
GRN	TNFRSF1B	psi-mi:“MI:0407”(direct interaction)	0.640
GRN	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.640
TNF	TNFRSF1B	psi-mi:“MI:0407”(direct interaction)	0.440
Traf1	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF1B	LTA	psi-mi:“MI:0915”(physical association)	0.400
LTA	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF1B	CD14	psi-mi:“MI:0915”(physical association)	0.370
ZNF420	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.370
TNFRSF1B	UBQLN1	psi-mi:“MI:0915”(physical association)	0.370
TNFRSF1B	MAP3K7	psi-mi:“MI:0914”(association)	0.350
TNFRSF1B	TCAF2	psi-mi:“MI:0914”(association)	0.350
	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.000
malT	TNFRSF1B	psi-mi:“MI:0915”(physical association)	0.000
TNFRSF1B	BAG2	psi-mi:“MI:0915”(physical association)	0.000
TNFRSF1B	AIFM1	psi-mi:“MI:0915”(physical association)	0.000
TNFRSF1B	KPNB1	psi-mi:“MI:0915”(physical association)	0.000
TNFRSF1B	HSPA1L	psi-mi:“MI:0915”(physical association)	0.000
TNFRSF1B	HSPA5	psi-mi:“MI:0915”(physical association)	0.000
TNFRSF1B	TRIP13	psi-mi:“MI:0915”(physical association)	0.000
TNFRSF1B	DBT	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (192): TNFRSF1B (Reconstituted Complex), CSNK1A1L (Reconstituted Complex), TNFRSF1B (Biochemical Activity), TNF (Reconstituted Complex), TNF (Reconstituted Complex), FANCD2 (Affinity Capture-MS), TNF (Affinity Capture-MS), TRAF2 (Affinity Capture-MS), RNF31 (Affinity Capture-Western), RBCK1 (Affinity Capture-Western), BIRC3 (Affinity Capture-Western), TRAF2 (Two-hybrid), TRAF2 (Reconstituted Complex), TNFRSF1B (Affinity Capture-Western), CAV1 (Affinity Capture-Western)

ESM2 similar proteins: D3ZF92, D5K8A9, O00220, O14763, O15553, O35305, O35714, O75509, P12342, P20333, P22934, P25118, P25119, P26898, P27987, P28908, P50284, P97525, Q2YDG7, Q3U4N7, Q5HZW5, Q5ND28, Q5PQX1, Q60846, Q80WY6, Q86T13, Q86VZ4, Q8BX35, Q8BZW2, Q8CB67, Q8IY92, Q8NC42, Q8TBE3, Q8VCP9, Q8WWF5, Q90VY2, Q921T2, Q96L08, Q9DA48, Q9EPU5

Diamond homologs: A5D7R1, D3ZF92, O00300, O08712, O08727, O35305, O75509, O95407, P0DTN0, P20333, P25119, P25942, P25943, P27512, P29825, P36941, P43489, P83626, Q28203, Q3LRP1, Q3ZTK5, Q63199, Q7YRL5, Q8SQ34, Q9EPU5, Q9Y6Q6, Q80WM9, O73559, P0DSV7, P0DSV8, P68636, P68637, P07174, P08138, P15725, P20334, P47741, P50284, Q07011, Q9Z0W1

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
VCB-Cul2	“down-regulates quantity by destabilization”	TNFRSF1B	polyubiquitination
ASB3	“down-regulates quantity by destabilization”	TNFRSF1B	binding
SMURF2	“up-regulates activity”	TNFRSF1B	ubiquitination
TNFRSF1B	up-regulates	TRAF1	binding
TNFRSF1B	up-regulates	TRAF1
TNFRSF1B	“up-regulates activity”	TRAF2	binding
TNF	“up-regulates activity”	TNFRSF1B	binding
TNFRSF1B	“up-regulates activity”	MAPK14

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 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
Gap junction trafficking and regulation	6	34.8×	2e-06
Gap junction trafficking	6	34.8×	2e-06
Formation of tubulin folding intermediates by CCT/TriC	5	25.8×	3e-05
RHO GTPases activate IQGAPs	6	25.3×	6e-06
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	5	24.9×	3e-05
Prefoldin mediated transfer of substrate to CCT/TriC	5	24.0×	3e-05
Eukaryotic Translation Elongation	7	23.8×	2e-06
Activation of AMPK downstream of NMDARs	5	23.2×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein refolding	6	39.8×	7e-06
erythrocyte differentiation	5	14.2×	3e-03
cytoplasmic translation	7	13.8×	4e-04
cellular response to type II interferon	6	13.3×	1e-03
positive regulation of protein ubiquitination	5	11.3×	5e-03
response to endoplasmic reticulum stress	6	10.7×	3e-03
translation	8	8.8×	9e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	5
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1714 predictions. Top by Δscore:

Variant	Effect	Δscore
1:12167167:CAGGT:C	donor_loss	1.0000
1:12167168:AGGT:A	donor_loss	1.0000
1:12167169:GGT:G	donor_loss	1.0000
1:12167170:G:A	donor_loss	1.0000
1:12167171:T:G	donor_loss	1.0000
1:12190951:CCTCA:C	acceptor_loss	1.0000
1:12190954:CAG:C	acceptor_loss	1.0000
1:12190955:A:AG	acceptor_gain	1.0000
1:12190956:G:GA	acceptor_gain	1.0000
1:12190956:GGCCA:G	acceptor_gain	1.0000
1:12191047:TTCCC:T	donor_gain	1.0000
1:12191086:G:GA	donor_loss	1.0000
1:12191086:G:GG	donor_gain	1.0000
1:12191087:T:A	donor_loss	1.0000
1:12191090:G:GG	donor_gain	1.0000
1:12192520:CAGAT:C	donor_gain	1.0000
1:12192521:AGATG:A	donor_loss	1.0000
1:12192522:GAT:G	donor_gain	1.0000
1:12192523:AT:A	donor_gain	1.0000
1:12192523:ATG:A	donor_loss	1.0000
1:12192524:TGT:T	donor_loss	1.0000
1:12192525:G:GG	donor_gain	1.0000
1:12192525:GTG:G	donor_loss	1.0000
1:12192526:TGA:T	donor_loss	1.0000
1:12192527:GAG:G	donor_loss	1.0000
1:12192861:A:AG	acceptor_gain	1.0000
1:12192862:G:GG	acceptor_gain	1.0000
1:12192862:GCT:G	acceptor_gain	1.0000
1:12193949:TTCTA:T	acceptor_loss	1.0000
1:12193950:TCTA:T	acceptor_loss	1.0000

AlphaMissense

2985 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:12192478:T:C	F169L	0.999
1:12192480:C:A	F169L	0.999
1:12192480:C:G	F169L	0.999
1:12192508:T:A	C179S	0.996
1:12192509:G:C	C179S	0.996
1:12192479:T:G	F169C	0.995
1:12192481:T:C	S170P	0.995
1:12192463:T:A	C164S	0.994
1:12192464:G:C	C164S	0.994
1:12191893:T:A	C143S	0.993
1:12191894:G:C	C143S	0.993
1:12192454:T:A	C161S	0.993
1:12192455:G:C	C161S	0.993
1:12192464:G:A	C164Y	0.992
1:12192465:T:G	C164W	0.992
1:12191055:T:A	C93S	0.991
1:12191056:G:C	C93S	0.991
1:12191794:T:A	C110S	0.991
1:12191795:G:C	C110S	0.991
1:12191875:T:A	C137S	0.991
1:12191876:G:C	C137S	0.991
1:12191893:T:C	C143R	0.991
1:12191902:G:T	G146C	0.991
1:12192508:T:C	C179R	0.991
1:12192509:G:A	C179Y	0.990
1:12191818:T:A	C118S	0.989
1:12191819:G:C	C118S	0.989
1:12192454:T:C	C161R	0.989
1:12192463:T:C	C164R	0.989
1:12188895:G:T	G60C	0.988

dbSNP variants (sampled 300 via entrez): RS1000021009 (1:12169090 G>A), RS1000128688 (1:12188559 A>C), RS1000211263 (1:12206381 A>G,T), RS1000319007 (1:12199838 G>A), RS1000414082 (1:12199513 C>G), RS1000431054 (1:12167655 GATTT>G), RS1000479454 (1:12188752 CA>C), RS1000497860 (1:12168162 T>C), RS1000645605 (1:12201459 C>A), RS1000673992 (1:12199514 C>T), RS1000728892 (1:12205551 G>A), RS1000730939 (1:12194960 G>A), RS1000740020 (1:12200976 G>C), RS1000798798 (1:12193621 T>C), RS1000886837 (1:12167846 A>G)

Disease associations

OMIM: gene MIM:191191 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000492	Abnormal eyelid morphology
HP:0000656	Ectropion
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000964	Eczematoid dermatitis
HP:0000969	Edema
HP:0000982	Palmoplantar keratoderma
HP:0000988	Skin rash
HP:0000989	Pruritus
HP:0001019	Erythroderma
HP:0001029	Poikiloderma
HP:0001053	Hypopigmented skin patches
HP:0001337	Tremor
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001945	Fever
HP:0002045	Hypothermia
HP:0002103	Abnormal pleura morphology
HP:0002240	Hepatomegaly
HP:0002665	Lymphoma
HP:0002716	Lymphadenopathy
HP:0002721	Immunodeficiency
HP:0002843	Abnormal T cell morphology
HP:0003202	Skeletal muscle atrophy
HP:0004332	Abnormal lymphocyte morphology
HP:0005561	Abnormal bone marrow cell morphology
HP:0007400	Irregular hyperpigmentation
HP:0007488	Diffuse skin atrophy

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST002827_1	Urate levels (BMI interaction)	9.000000e-06
GCST004923_1	Tuberculosis	1.000000e-11
GCST006585_2454	Blood protein levels	7.000000e-08
GCST009731_19	Blood protein levels in cardiovascular risk	7.000000e-14
GCST009798_30	Asthma	8.000000e-13
GCST90002381_564	Eosinophil count	9.000000e-18
GCST90002382_60	Eosinophil percentage of white cells	6.000000e-17

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004531	urate measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1250356 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1061622	Efficacy	3	infliximab;Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis
rs1061622	Efficacy	3	etanercept	Spondylitis;Ankylosing
rs1061631	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis
rs3397	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3397	TNFRSF1B	3	5.50	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs1061622	TNFRSF1B	3	5.75	2	etanercept;infliximab;Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs1061624	TNFRSF1B		0.00	0
rs1061631	TNFRSF1B	3	0.00	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Tumour necrosis factor (TNF) receptor family

ChEMBL bioactivities

1 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.49	Kd	320.7	nM	CHEMBL5414162

PubChem BioAssay actives

1 with measured affinity, of 5 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S,3R)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-aminopropanoyl]amino]-3-sulfanylpropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid	1989567: Inhibition of TNF-alpha (unknown origin) binding to TNFR2 assessed as dissociation constant of TNF-alpha preincubated for 15 mins by MST assay (Rvb = 30.5 nM)	kd	0.3207	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, affects cotreatment, decreases expression	3
(+)-JQ1 compound	affects cotreatment, increases expression, decreases expression	3
Nickel	decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
Particulate Matter	decreases expression, increases expression	3
Decitabine	affects expression, increases expression	2
Arsenic Trioxide	increases expression, affects cotreatment, decreases expression	2
Acetaminophen	affects cotreatment, increases expression	2
Ethanol	decreases reaction, increases expression	2
Arsenic	affects expression, affects methylation	2
Vehicle Emissions	affects cotreatment, increases expression	2
Lipopolysaccharides	affects cotreatment, increases expression, decreases reaction	2
Tetradecanoylphorbol Acetate	affects cotreatment, decreases expression, decreases reaction, increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
Asian ginseng	affects cotreatment, increases expression	1
lly-283	decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
sanguinarine	affects cotreatment, increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	increases expression	1
butylphen	increases expression	1
alfacalcidol	decreases expression	1
lead acetate	affects cotreatment, decreases expression	1
alpha-naphthoflavone	decreases reaction, increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
quercitrin	decreases expression	1
beta-lapachone	decreases expression	1
chromous chloride	affects cotreatment, decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1250028	Binding	Binding affinity to human Tumor necrosis factor receptor 2 by surface plasmon resonance method	C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L. — Nat Chem Biol

Cellosaurus cell lines

16 cell lines: 7 transformed cell line, 7 cancer cell line, 2 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A8CL	HEK-Blue IL-1beta	Transformed cell line	Female
CVCL_A8CM	HEK-Blue IL-1R	Transformed cell line	Female
CVCL_B8A0	Abcam Raji TNFRSF1B KO	Cancer cell line	Male
CVCL_C0AU	Abcam THP-1 TNFRSF1B KO	Cancer cell line	Male
CVCL_C7CH	Abcam PC-3 TNFRSF1B KO	Cancer cell line	Male
CVCL_E0RP	Ubigene HeLa TNFRSF1B KO	Cancer cell line	Female
CVCL_E6S4	Genomeditech CHO-K1 H_TNFRSF1B(TNFR2)	Spontaneously immortalized cell line	Female
CVCL_E6V7	Genomeditech HEK-293 H_TNFRSF1B(TNFR2)	Transformed cell line	Female
CVCL_E6W1	Genomeditech Jurkat H_TNFRSF1B(TNFR2) Reporter	Cancer cell line	Male
CVCL_E8DC	HEK-Blue IL-1beta v2	Transformed cell line	Female

Clinical trials (associated diseases)

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