TNFAIP3

Summary

TNFAIP3 (TNF alpha induced protein 3, HGNC:11896) is a protein-coding gene on chromosome 6q23.3, encoding Tumor necrosis factor alpha-induced protein 3 (P21580). Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities.

This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded by this gene is a zinc finger protein and ubiqitin-editing enzyme, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. The encoded protein, which has both ubiquitin ligase and deubiquitinase activities, is involved in the cytokine-mediated immune and inflammatory responses. Several transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 7128 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoinflammatory syndrome, familial, Behcet-like 1 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 69
• Clinical variants (ClinVar): 664 total — 59 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 57
• Druggable target: yes
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_001270508

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11896
Approved symbol	TNFAIP3
Name	TNF alpha induced protein 3
Location	6q23.3
Locus type	gene with protein product
Status	Approved
Aliases	A20, OTUD7C
Ensembl gene	ENSG00000118503
Ensembl biotype	protein_coding
OMIM	191163
Entrez	7128

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000237289, ENST00000420009, ENST00000421450, ENST00000433680, ENST00000485192, ENST00000612899, ENST00000698329, ENST00000698330, ENST00000711061, ENST00000906237, ENST00000906238, ENST00000906239, ENST00000906240, ENST00000906241, ENST00000906242, ENST00000971893, ENST00000971894

RefSeq mRNA: 3 — MANE Select: NM_001270508 NM_001270507, NM_001270508, NM_006290

CCDS: CCDS5187

Canonical transcript exons

ENST00000612899 — 9 exons

Exon	Start	End
ENSE00001724607	137871213	137871522
ENSE00003733698	137867259	137867542
ENSE00003890364	137881035	137883312
ENSE00003973308	137880071	137880252
ENSE00003973315	137877076	137877256
ENSE00003973317	137875996	137876166
ENSE00003973318	137878432	137879351
ENSE00003973319	137875688	137875835
ENSE00003973321	137874845	137875035

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 99.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 144.1406 / max 9847.9962, expressed in 1708 samples.

FANTOM5 promoters (28 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70038	127.7361	1652
70037	3.9321	1148
70056	3.4486	352
70053	2.0969	343
70051	0.8280	264
70039	0.7934	180
70072	0.5604	225
70074	0.5515	207
70068	0.5301	135
70059	0.4694	162

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vena cava	UBERON:0004087	99.05	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.20	gold quality
vermiform appendix	UBERON:0001154	97.51	gold quality
epithelium of nasopharynx	UBERON:0001951	97.46	gold quality
pericardium	UBERON:0002407	97.34	gold quality
mucosa of urinary bladder	UBERON:0001259	97.05	gold quality
upper leg skin	UBERON:0004262	96.77	gold quality
thymus	UBERON:0002370	96.21	gold quality
caecum	UBERON:0001153	96.18	gold quality
lymph node	UBERON:0000029	95.96	gold quality
cartilage tissue	UBERON:0002418	95.90	gold quality
bone marrow cell	CL:0002092	95.59	gold quality
trachea	UBERON:0003126	95.43	gold quality
right ovary	UBERON:0002118	95.21	gold quality
pancreatic ductal cell	CL:0002079	94.93	gold quality
visceral pleura	UBERON:0002401	94.93	gold quality
left ovary	UBERON:0002119	94.79	gold quality
bronchus	UBERON:0002185	94.75	gold quality
epithelium of bronchus	UBERON:0002031	94.60	gold quality
urethra	UBERON:0000057	94.48	gold quality
bronchial epithelial cell	CL:0002328	94.29	gold quality
nasal cavity epithelium	UBERON:0005384	94.25	gold quality
palpebral conjunctiva	UBERON:0001812	93.94	gold quality
mononuclear cell	CL:0000842	93.86	gold quality
saphenous vein	UBERON:0007318	93.81	gold quality
monocyte	CL:0000576	93.76	gold quality
pylorus	UBERON:0001166	93.75	gold quality
gall bladder	UBERON:0002110	93.65	gold quality
pleura	UBERON:0000977	93.61	gold quality
leukocyte	CL:0000738	93.50	gold quality

Single-cell (SCXA)

Detected in 30 experiment(s), a significant marker in 22.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	5503.51
E-CURD-122	yes	3753.75
E-MTAB-7052	yes	3287.33
E-CURD-120	yes	2587.87
E-HCAD-15	yes	2488.39
E-MTAB-10855	yes	2299.93
E-CURD-46	yes	2209.08
E-MTAB-9467	yes	2143.64
E-CURD-88	yes	1536.06
E-GEOD-139324	yes	948.14
E-HCAD-1	yes	865.20
E-CURD-6	yes	712.38
E-CURD-79	yes	707.31
E-HCAD-4	yes	76.10
E-MTAB-9221	yes	27.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
IRF7	Repression
JUN	Repression
NFKB1	Repression
RELA	Repression
SATB1	Unknown

Upstream regulators (CollecTRI, top): CEBPA, CEBPB, FOXL2, NFKB1, NFKB, NFKBIA, PITX2, PITX3, PML, REL, RELA, RELB, SATB1, SPI1, TFAP2A, USF1

miRNA regulators (miRDB)

117 targeting TNFAIP3, 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-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-335-3P	99.93	73.36	4958

Literature-anchored findings (GeneRIF, showing 40)

• Corto interacts with Polycomb-group proteins and the GAGA factor. (PMID:12771214)
• Corto and DSP1 proteins co-localize at 91 sites on polytene chromosomes and co-immunoprecipitate in embryos. (PMID:16613610)
• interaction between the Enhancer of Trithorax and Polycomb Corto and Cyclin G is involved in regulating the balance between cell proliferation and cell differentiation during abdominal epithelium development (PMID:18667003)
• results reveal a novel epigenetic mechanism involving Corto and Piwi that defines the fate and signaling function of niche cells in maintaining germline stem cells (PMID:20647505)
• Corto, rl and dMP1 interact during wing tissue differentiation; Corto, ERK(rl) and dMP1 form a complex in the nucleus and co-localize on several sites on polytene chromosomes (PMID:21401930)
• Elongin C and Corto bind the vein-promoting gene. (PMID:24204884)
• Enhancer of trithorax/polycomb, Corto, regulates timing of hunchback gene relocation and competence in Drosophila neuroblasts. (PMID:35177098)
• The zinc finger protein A20 is an NF-kappaB-inducible gene that can protect the IKKgamma-deficient cells from TNF-induced apoptosis by disrupting the recruitment of the death domain signaling molecules TRADD and RIP to the receptor signaling complex. (PMID:12167698)
• In vitro, recombinant A20 inhibits NF-kappaB activation in mouse islets and protects from cytokine- and death receptor-mediated apoptosis; in vivo, A20 preserves mouse islet cell mass and function in diabetic mice in early post-transplantation period. (PMID:12794157)
• redundant and distinct roles in regulating NFkappaB activation and apoptosis (PMID:14754897)
• Our results suggest that A20 may function as a negative regulator of TLR-mediated inflammatory responses in the airway, thereby protecting the host against harmful overresponses to pathogens. (PMID:15142865)
• A20 also protects from Fas/CD95 and significantly blunts natural killer cell-mediated endothelial cell apoptosis by inhibiting caspase 8 activation (PMID:15251990)
• definition of a novel ubiquitin ligase domain and identification of two sequential mechanisms by which A20 downregulates NF-kappaB signalling (PMID:15258597)
• A20 is a candidate negative regulator of the signaling cascade to interferon regulatory factor-3 activation in the innate antiviral response. (PMID:15661910)
• A20 may be involved in the regulation of cell proliferation by tumor necrosis factor, Vitamin D, and androgen in prostate cancer. (PMID:15862966)
• A1 and A20 are both required for optimal protection from apoptosis (A1) and inflammation (A20) in conditions leading to renal damage (PMID:16164629)
• the virus-inducible, NF-kappaB-dependent activation of A20 functions as a negative regulator of RIG-I-mediated induction of the antiviral state (PMID:16306043)
• Results suggest that A20 can effectively protect neurons from postischemic apoptosis and may function partly on death receptor caspase pathway. (PMID:16474993)
• ABIN-1 physically links A20 to NEMO/IKKgamma and facilitates A20-mediated de-ubiquitination of NEMO/IKKgamma, thus resulting in inhibition of NF-kappaB (PMID:16684768)
• A20 prevents neointimal hyperplasia through combined anti-inflammatory and antiproliferative functions in medial smooth muscle cells. (PMID:16816117)
• A new role for A20 in regulating neovascularisation. We used RNA interference to inhibit A20 expression in primary human umbilical vein endothelial cells (HUVECs)and investigated the effect on tubule formation in two in vitro angiogenesis assays (PMID:16824518)
• Using oligonucleotide microarrays and real-time PCR, we identified TNFAIP3/A20 as the most highly regulated antiapoptotic gene expressed in cytokine-stimulated human and mouse islets. (PMID:16936197)
• These findings point to variability in the A20/TNFAIP3 gene as a modulator of CAD risk in type 2 diabetes. This effect is mediated by allelic differences in A20 expression. (PMID:17259397)
• A20 is a new 17beta-estradiol-regulated gene. (PMID:17297453)
• May act as a tumor suppressor gene in ocular adnexal marginal zone B cell lymphoma; loss of this gene may play an important role in lymphomagenesis. (PMID:17886247)
• A20 and HO-1 may play protective role in acute graft rejection. (PMID:17953374)
• analysis of the crystal structure of the N-terminal OTU (ovarian tumour) deubiquitinase domain of A20 (PMID:17961127)
• These findings reveal a dynamic regulation of DSIF involving either E-box or NF-kappaB depending on the physiological circumstances. (PMID:17962196)
• Molecular basis for the unique deubiquitinating activity of the NF-kapppaB inhibitor A20 is reported. (PMID:18164316)
• results further define the molecular mechanisms that control activation of NF-kappaB and reveal a function for A20 in the regulation of CARMA and BCL10 activity in lymphoid and non-lymphoid cells (PMID:18349075)
• Pre-treatment of human umbilical vein endothelial cells with an adenovirus containing A20 suppressed activation of NF-kappaB and induction of pro-inflammatory molecules by hypoxia/re-oxygenation. (PMID:18813897)
• five genes (TNFSF10/TRAIL, IL1RN, IFI27, GZMB, and CCR5) were upregulated and three genes (CLK1, TNFAIP3 and BTG1) were downregulated in at least three out of four subpopulations during acute GVHD. (PMID:18814951)
• evidence that the RA/SLE locus 6q23/TNFAIP3 is a newly identified T1D locus. (PMID:19110536)
• Dendritic cells downregulated by A20 show higher activation of transcription factors NF-kappaB and activator protein-1, which results in increased and sustained production of interleukin (IL)-6, IL-10, and IL-12p70. (PMID:19124729)
• RNF11, together with TAX1BP1 and Itch, is an essential component of an A20 ubiquitin-editing protein complex that ensures transient activation of inflammatory signalling pathways. (PMID:19131965)
• TNFalpha triggers both caspase 8-dependent and -independent cell death pathways in macrophages and identify a novel mechanism by which A20 protects these cells against both pathways. (PMID:19152111)
• These results establish that variants near TNFAIP3 contribute to differential risk of SLE and RA. (PMID:19165918)
• We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry (PMID:19165919)
• Expanded catalog of genetic loci implicated in psoriasis susceptibility. (PMID:19169254)
• Both TNFAIP3 (A20, at the protein level) and REL are key mediators in the nuclear factor kappa B (NF-kappaB) inflammatory signalling pathway. (PMID:19240061)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnfaip3	ENSDARG00000027777
mus_musculus	Tnfaip3	ENSMUSG00000019850
rattus_norvegicus	Tnfaip3	ENSRNOG00000049517

Paralogs (2): OTUD7A (ENSG00000169918), OTUD7B (ENSG00000264522)

Protein

Protein identifiers

Tumor necrosis factor alpha-induced protein 3 — P21580 (reviewed: P21580)

Alternative names: OTU domain-containing protein 7C, Putative DNA-binding protein A20, Zinc finger protein A20

All UniProt accessions (5): A0AA34QW12, P21580, Q5VXQ8, Q5VXQ9, Q5VXR0

UniProt curated annotations — full annotation on UniProt →

Function. Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities. Involved in immune and inflammatory responses signaled by cytokines, such as TNF and IL-1 beta, or pathogens via Toll-like receptors (TLRs) through terminating NF-kappa-B activity. Essential component of a ubiquitin-editing protein complex, comprising also RNF11, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. In cooperation with TAX1BP1 promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In cooperation with TAX1BP1 promotes ubiquitination of UBE2N and proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation, deubiquitinates ‘Lys-63’-polyubiquitin chains on RIPK1 and catalyzes the formation of ‘Lys-48’-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NF-kappa-B. Deubiquitinates TRAF6 probably acting on ‘Lys-63’-linked polyubiquitin. Upon T-cell receptor (TCR)-mediated T-cell activation, deubiquitinates ‘Lys-63’-polyubiquitin chains on MALT1 thereby mediating disassociation of the CBM (CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK activation. Deubiquitinates NEMO/IKBKG; the function is facilitated by TNIP1 and leads to inhibition of NF-kappa-B activation. Upon stimulation by bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also inhibit I-kappa-B-kinase (IKK) through a non-catalytic mechanism which involves polyubiquitin; polyubiquitin promotes association with IKBKG and prevents IKK MAP3K7-mediated phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able to deubiquitinate ‘Lys-11’-, ‘Lys-48’- and ‘Lys-63’ polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system. Required for LPS-induced production of pro-inflammatory cytokines and IFN beta in LPS-tolerized macrophages.

Subunit / interactions. Homodimer. Interacts with TNIP1, TAX1BP1 and TRAF2. Interacts with RNF11, ITCH and TAX1BP1 only after TNF stimulation; these interaction are transient and they are lost after 1 hour of stimulation with TNF. Interacts with YWHAZ and YWHAH. Interacts with IKBKG; the interaction is induced by TNF stimulation and by polyubiquitin. Interacts with RIPK1. Interacts with UBE2N; the interaction requires TAX1BP1. Interacts with TRAF6; the interaction is inhibited by HTLV-1 protein Tax.

Subcellular location. Cytoplasm. Nucleus. Lysosome Cytoplasm.

Post-translational modifications. Proteolytically cleaved by MALT1 upon TCR stimulation; disrupts NF-kappa-B inhibitory function and results in increased IL-2 production. It is proposed that only a fraction of TNFAIP3 colocalized with TCR and CBM complex is cleaved, leaving the main TNFAIP3 pool intact.

Disease relevance. Autoinflammatory syndrome, familial, Behcet-like 1 (AIFBL1) [MIM:616744] An autosomal dominant, autoinflammatory disorder with early onset, characterized by ulceration of mucosal surfaces, particularly in the oral and genital areas. Additional variable features include skin rash, uveitis, and polyarthritis. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The A20-type zinc fingers mediate the ubiquitin ligase activity. The A20-type zinc finger 4 selectively recognizes ‘Lys-63’-linked polyubiquitin. The A20-type zinc finger 4-7 are sufficient to bind polyubiquitin. The OTU domain mediates the deubiquitinase activity.

Induction. By TNF.

Similarity. Belongs to the peptidase C64 family.

RefSeq proteins (3): NP_001257436, NP_001257437, NP_006281 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002653	Znf_A20	Domain
IPR003323	OTU_dom	Domain
IPR051346	OTU_Deubiquitinase	Family

Pfam: PF01754, PF02338

UniProt features (139 total): binding site 28, mutagenesis site 25, helix 22, strand 22, region of interest 14, zinc finger region 7, modified residue 4, sequence variant 4, chain 3, active site 3, turn 2, compositionally biased region 2, initiator methionine 1, domain 1, site 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
3VUX	X-RAY DIFFRACTION	1.7
3ZJE	X-RAY DIFFRACTION	1.84
3ZJD	X-RAY DIFFRACTION	1.87
3ZJG	X-RAY DIFFRACTION	1.92
3VUW	X-RAY DIFFRACTION	1.95
3VUY	X-RAY DIFFRACTION	1.98
3ZJF	X-RAY DIFFRACTION	2.2
3DKB	X-RAY DIFFRACTION	2.5
3OJ3	X-RAY DIFFRACTION	2.5
5V3P	X-RAY DIFFRACTION	2.5
5LRX	X-RAY DIFFRACTION	2.85
5V3B	X-RAY DIFFRACTION	3
2VFJ	X-RAY DIFFRACTION	3.2
3OJ4	X-RAY DIFFRACTION	3.4
2EQE	SOLUTION NMR
2EQF	SOLUTION NMR
2EQG	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P21580-F1	74.86	0.37

Functional residue map

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

Catalytic / active sites (4): 100; 103 (nucleophile); 256 (proton acceptor); 439–440 (cleavage; by malt1)

Ligand- & substrate-binding residues (28): 387; 392; 404; 407; 478; 483; 495; 498; 521; 524; 536; 539 …

Post-translational modifications (4): 2, 459, 575, 645

Mutagenesis-validated functional residues (25):

Position	Phenotype
70	minor effect on ’lys-48’ deubiquitinase activity. strongly reduced ’lys-63’ deubiquitinase activity.
97	minor effect on ’lys-48’ deubiquitinase activity.
100	strongly reduced deubiquitinase activity.
103	loss of deubiquitinase activity.
103	loss of ’lys-63’ deubiquitinating activity. down-regulation of tnf-induced nf-kappa-b activity less effective.
106	reduces deubiquitinase activity.
157	strongly reduced ’lys-48’ deubiquitinase activity.
159	strongly reduced ’lys-48’ deubiquitinase activity.
190	strongly reduced ’lys-48’ deubiquitinase activity.
192	strongly reduced ’lys-48’ deubiquitinase activity.
224	strongly reduced ’lys-48’ deubiquitinase activity.
227	strongly reduced ’lys-48’ deubiquitinase activity.
256	loss of deubiquitinase activity.
521	no effect on ubiquitin ligase activity; when associated with a-524.
524	no effect on ubiquitin ligase activity; when associated with a-521.
562	abolishes interactionj with ywhaz and ywhah; no effect on inhibitory activity of tnf-induced nf-kappa-b activation.
565	abolishes interactionj with ywhaz and ywhah; no effect on inhibitory activity of tnf-induced nf-kappa-b activation.
614	impairs ubiquitination activity. loss of down-regulation of nf-kappa-b activity; when associated with a-615 or r-626.
615	impairs ubiquitination activity. loss of down-regulation of nf-kappa-b activity; when associated with a-614.
624	marked attenuation of ubiquitin ligase activity and inhibition of ripk1 degradation; when associated with a-627.
626	impairs ubiquitination activity. loss of down-regulation of nf-kappa-b activity; when associated with a-614.
627	marked attenuation of ubiquitin ligase activity and inhibition of ripk1 degradation; when associated with a-624.
770–771	impairs polyubiquitin binding, abolishes inhibition of ikk activation.
779	impairs polyubiquitin binding, abolishes inhibition of ikk activation; when associated with a-782.
782	impairs polyubiquitin binding, abolishes inhibition of ikk activation; when associated with a-779.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-168638	NOD1/2 Signaling Pathway
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-5689896	Ovarian tumor domain proteases
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling

MSigDB gene sets: 878 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE45365_NK_CELL_VS_BCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, BIOCARTA_TNFR2_PATHWAY, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_HEPATOCYTE_PROLIFERATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM

GO Biological Process (53): B-1 B cell homeostasis (GO:0001922), response to molecule of bacterial origin (GO:0002237), regulation of germinal center formation (GO:0002634), negative regulation of chronic inflammatory response (GO:0002677), apoptotic process (GO:0006915), inflammatory response (GO:0006954), cytoskeleton organization (GO:0007010), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), cell migration (GO:0016477), protein deubiquitination (GO:0016579), positive regulation of Wnt signaling pathway (GO:0030177), negative regulation of protein ubiquitination (GO:0031397), response to muramyl dipeptide (GO:0032495), negative regulation of interleukin-1 beta production (GO:0032691), negative regulation of interleukin-2 production (GO:0032703), negative regulation of interleukin-6 production (GO:0032715), negative regulation of tumor necrosis factor production (GO:0032720), negative regulation of toll-like receptor 2 signaling pathway (GO:0034136), negative regulation of toll-like receptor 3 signaling pathway (GO:0034140), negative regulation of toll-like receptor 4 signaling pathway (GO:0034144), negative regulation of toll-like receptor 5 signaling pathway (GO:0034148), protein K11-linked deubiquitination (GO:0035871), nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway (GO:0035872), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), positive regulation of protein catabolic process (GO:0045732), negative regulation of bone resorption (GO:0045779), negative regulation of innate immune response (GO:0045824), negative regulation of smooth muscle cell proliferation (GO:0048662), regulation of defense response to virus by host (GO:0050691), negative regulation of inflammatory response (GO:0050728), negative regulation of B cell activation (GO:0050869), regulation of vascular wound healing (GO:0061043), cellular response to hydrogen peroxide (GO:0070301), negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway (GO:0070429), negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway (GO:0070433), protein K63-linked deubiquitination (GO:0070536), protein K48-linked ubiquitination (GO:0070936), protein K48-linked deubiquitination (GO:0071108), cellular response to lipopolysaccharide (GO:0071222), protein deubiquitination involved in ubiquitin-dependent protein catabolic process (GO:0071947)

GO Molecular Function (18): protease binding (GO:0002020), DNA binding (GO:0003677), ubiquitin-protein transferase activity (GO:0004842), cysteine-type deubiquitinase activity (GO:0004843), zinc ion binding (GO:0008270), kinase binding (GO:0019900), identical protein binding (GO:0042802), ubiquitin binding (GO:0043130), K63-linked deubiquitinase activity (GO:0061578), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), catalytic activity (GO:0003824), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), transferase activity (GO:0016740), hydrolase activity (GO:0016787), enzyme binding (GO:0019899), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), lysosome (GO:0005764), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
TNF signaling	3
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Deubiquitination	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cytokine production	2
negative regulation of immune system process	2
negative regulation of signal transduction	2
enzyme binding	2
deubiquitinase activity	2
protein binding	2
catalytic activity	2
cellular anatomical structure	2
B cell homeostasis	1
response to bacterium	1
response to external biotic stimulus	1
germinal center formation	1
regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of anatomical structure morphogenesis	1
chronic inflammatory response	1
regulation of chronic inflammatory response	1
negative regulation of inflammatory response	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
defense response	1
organelle organization	1
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
cell motility	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
positive regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
response to nitrogen compound	1
response to oxygen-containing compound	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
negative regulation of interleukin-1 production	1
interleukin-2 production	1
regulation of interleukin-2 production	1

Protein interactions and networks

STRING

3126 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFAIP3	TNIP1	Q15025	997
TNFAIP3	TNIP2	Q8NFZ5	985
TNFAIP3	RNF11	Q9Y3C5	905
TNFAIP3	TRAF6	Q9Y4K3	904
TNFAIP3	TRAF1	Q13077	895
TNFAIP3	NFKB1	P19838	832
TNFAIP3	CARD11	Q9BXL7	822
TNFAIP3	TAX1BP1	Q86VP1	810
TNFAIP3	OLIG3	Q7RTU3	801
TNFAIP3	PTPN22	Q9Y2R2	789
TNFAIP3	IRF5	Q13568	785
TNFAIP3	IKBKG	Q9Y6K9	785
TNFAIP3	TRAF3	Q13114	763
TNFAIP3	NFKBIA	P25963	733
TNFAIP3	TRAF3IP2	O43734	728

IntAct

141 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
TNFAIP3	TNIP1	psi-mi:“MI:0915”(physical association)	0.930
TNIP1	TNFAIP3	psi-mi:“MI:0915”(physical association)	0.930
TNFAIP3	TNFAIP3	psi-mi:“MI:0915”(physical association)	0.890
TNFAIP3	TRAF2	psi-mi:“MI:0915”(physical association)	0.870
TRAF2	TNFAIP3	psi-mi:“MI:0915”(physical association)	0.870
TNFAIP3	TAX1BP1	psi-mi:“MI:0915”(physical association)	0.810
TNFAIP3	IKBKG	psi-mi:“MI:0915”(physical association)	0.810
IKBKG	TNFAIP3	psi-mi:“MI:0915”(physical association)	0.810
IKBKG	TNFAIP3	psi-mi:“MI:0914”(association)	0.810
TNFAIP3	YWHAG	psi-mi:“MI:0915”(physical association)	0.730
TNFAIP3	TRIM23	psi-mi:“MI:0915”(physical association)	0.720
TNFAIP3	ARRDC3	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (449): TNFAIP3 (Two-hybrid), TNIP1 (Two-hybrid), YWHAQ (Two-hybrid), RNF114 (Two-hybrid), TNFAIP3 (Reconstituted Complex), RNF114 (Reconstituted Complex), TNFAIP3 (Affinity Capture-Western), RNF114 (Affinity Capture-Western), TNFAIP3 (Biochemical Activity), UBE2D1 (Reconstituted Complex), TNFAIP3 (Two-hybrid), TNFAIP3 (Two-hybrid), TRAF2 (Two-hybrid), TNIP1 (Two-hybrid), ARRDC3 (Two-hybrid)

ESM2 similar proteins: A2AWP8, A2RRU4, A4Q9F4, A6QM06, O95267, P0C0T1, P21580, P97260, Q12770, Q13572, Q14161, Q14CM0, Q29RM4, Q2TBA3, Q3UGM2, Q496Y0, Q4R8W3, Q5MNU5, Q5R5M3, Q5T6S3, Q5XI70, Q60769, Q66H91, Q66T02, Q68FF6, Q69ZK0, Q6GQT6, Q6P9L4, Q6RFZ7, Q6ZPY2, Q6ZWH5, Q70CQ1, Q70EL4, Q70Z35, Q8BYN3, Q8HXH0, Q8NHH1, Q8TBP0, Q8TCU6, Q96GD3

Diamond homologs: A0JMQ9, A6QP16, B1H2Q2, B2RUR8, P21580, Q4R8W3, Q5U595, Q60769, Q6GQQ9, Q6NUB7, Q7M760, Q8R554, Q8TE49, Q9UGI0, Q9VH90

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
TNFAIP3	“down-regulates activity”	TRAF6	deubiquitination
ITCH	“up-regulates activity”	TNFAIP3	binding
TNFAIP3	“down-regulates quantity”	RIPK1	ubiquitination
TAX1BP1	“up-regulates activity”	TNFAIP3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 69 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
Activation of BAD and translocation to mitochondria	7	104.5×	2e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	92.2×	3e-11
Regulation of NF-kappa B signaling	7	87.1×	4e-11
TICAM1, RIP1-mediated IKK complex recruitment	7	82.5×	6e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	79.0×	2e-09
TNF signaling	9	74.6×	3e-13
Caspase activation via Death Receptors in the presence of ligand	5	74.6×	1e-07
Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	5	74.6×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
toll-like receptor 3 signaling pathway	5	92.1×	4e-07
canonical NF-kappaB signal transduction	10	60.1×	3e-13
negative regulation of canonical NF-kappaB signal transduction	13	36.6×	2e-14
tumor necrosis factor-mediated signaling pathway	6	32.5×	5e-06
extrinsic apoptotic signaling pathway	5	25.1×	1e-04
obsolete positive regulation of NF-kappaB transcription factor activity	6	20.2×	5e-05
positive regulation of protein ubiquitination	5	17.5×	6e-04
positive regulation of canonical NF-kappaB signal transduction	14	16.7×	2e-11

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — DLBCLNOS.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	59
Likely pathogenic	16
Uncertain significance	331
Likely benign	197
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1319978	NM_001270508.2(TNFAIP3):c.1727dup (p.His577fs)	Pathogenic
1356180	NM_001270508.2(TNFAIP3):c.1904_1905del (p.Lys635fs)	Pathogenic
1365070	NM_001270508.2(TNFAIP3):c.1748G>A (p.Gly583Glu)	Pathogenic
1385222	NM_001270508.2(TNFAIP3):c.224_225dup (p.Thr76fs)	Pathogenic
1400308	NM_001270508.2(TNFAIP3):c.468dup (p.Leu157fs)	Pathogenic
1452189	NM_001270508.2(TNFAIP3):c.1004T>A (p.Leu335Ter)	Pathogenic
1452211	NM_001270508.2(TNFAIP3):c.971_975del (p.Leu324fs)	Pathogenic
1453081	NM_001270508.2(TNFAIP3):c.90del (p.Phe30fs)	Pathogenic
1453756	NM_001270508.2(TNFAIP3):c.120del (p.Phe40fs)	Pathogenic
1456622	NM_001270508.2(TNFAIP3):c.1097_1098del (p.Glu366fs)	Pathogenic
1456817	NM_001270508.2(TNFAIP3):c.133C>T (p.Arg45Ter)	Pathogenic
1676287	NM_001270508.2(TNFAIP3):c.1346del (p.Asn449fs)	Pathogenic
1676288	NM_001270508.2(TNFAIP3):c.1428G>A (p.Met476Ile)	Pathogenic
1711639	NM_001270508.2(TNFAIP3):c.105del (p.Ile36fs)	Pathogenic
1723128	NM_001270508.2(TNFAIP3):c.1694C>G (p.Ser565Ter)	Pathogenic
1992904	NM_001270508.2(TNFAIP3):c.1368dup (p.Pro457fs)	Pathogenic
1996272	NM_001270508.2(TNFAIP3):c.1069C>T (p.Gln357Ter)	Pathogenic
2030275	NM_001270508.2(TNFAIP3):c.1722dup (p.Ser575fs)	Pathogenic
2036768	NM_001270508.2(TNFAIP3):c.948del (p.Trp317fs)	Pathogenic
2068888	NM_001270508.2(TNFAIP3):c.235del (p.Ser79fs)	Pathogenic
2090064	NM_001270508.2(TNFAIP3):c.2089A>T (p.Arg697Ter)	Pathogenic
2109776	NM_001270508.2(TNFAIP3):c.349del (p.Asp117fs)	Pathogenic
219110	NM_001270508.2(TNFAIP3):c.811C>T (p.Arg271Ter)	Pathogenic
219112	NM_001270508.2(TNFAIP3):c.918C>G (p.Tyr306Ter)	Pathogenic
2499023	NM_001270508.2(TNFAIP3):c.1836C>A (p.Cys612Ter)	Pathogenic
2701572	NM_001270508.2(TNFAIP3):c.1225G>T (p.Glu409Ter)	Pathogenic
2711364	NM_001270508.2(TNFAIP3):c.1068G>A (p.Trp356Ter)	Pathogenic
2824135	NM_001270508.2(TNFAIP3):c.872T>A (p.Leu291Ter)	Pathogenic
2837632	NM_001270508.2(TNFAIP3):c.1449C>A (p.Cys483Ter)	Pathogenic
2840851	NM_001270508.2(TNFAIP3):c.1068_1069delinsAA (p.Trp356_Gln357delinsTer)	Pathogenic

SpliceAI

1671 predictions. Top by Δscore:

Variant	Effect	Δscore
6:137871208:TTCA:T	acceptor_loss	1.0000
6:137871210:CAG:C	acceptor_loss	1.0000
6:137871211:A:AG	acceptor_gain	1.0000
6:137871211:AG:A	acceptor_gain	1.0000
6:137871211:AGGT:A	acceptor_gain	1.0000
6:137871212:G:GT	acceptor_gain	1.0000
6:137871212:GG:G	acceptor_gain	1.0000
6:137871212:GGT:G	acceptor_gain	1.0000
6:137871212:GGTG:G	acceptor_gain	1.0000
6:137871212:GGTGT:G	acceptor_gain	1.0000
6:137871518:GAACG:G	donor_gain	1.0000
6:137871519:AACG:A	donor_gain	1.0000
6:137871520:ACG:A	donor_gain	1.0000
6:137871520:ACGGT:A	donor_loss	1.0000
6:137871521:CG:C	donor_gain	1.0000
6:137871521:CGG:C	donor_loss	1.0000
6:137871522:GG:G	donor_gain	1.0000
6:137871522:GGTAA:G	donor_loss	1.0000
6:137871523:G:GG	donor_gain	1.0000
6:137871524:T:A	donor_loss	1.0000
6:137874836:T:TA	acceptor_gain	1.0000
6:137874840:CTCA:C	acceptor_loss	1.0000
6:137874843:A:AG	acceptor_gain	1.0000
6:137874843:AG:A	acceptor_gain	1.0000
6:137874843:AGGT:A	acceptor_gain	1.0000
6:137874843:AGGTG:A	acceptor_loss	1.0000
6:137874844:G:GA	acceptor_gain	1.0000
6:137874844:GG:G	acceptor_gain	1.0000
6:137874844:GGT:G	acceptor_gain	1.0000
6:137874844:GGTG:G	acceptor_gain	1.0000

AlphaMissense

5264 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:137881230:T:A	C762S	1.000
6:137881230:T:C	C762R	1.000
6:137881231:G:C	C762S	1.000
6:137878488:T:C	L348P	0.999
6:137878491:T:A	V349D	0.999
6:137878604:T:A	C387S	0.999
6:137878604:T:C	C387R	0.999
6:137878605:G:C	C387S	0.999
6:137878619:T:C	C392R	0.999
6:137878655:T:A	C404S	0.999
6:137878655:T:C	C404R	0.999
6:137878656:G:C	C404S	0.999
6:137878892:T:C	C483R	0.999
6:137881232:C:G	C762W	0.999
6:137881245:T:A	C767S	0.999
6:137881245:T:C	C767R	0.999
6:137881246:G:A	C767Y	0.999
6:137881246:G:C	C767S	0.999
6:137881247:T:G	C767W	0.999
6:137881281:T:A	C779S	0.999
6:137881281:T:C	C779R	0.999
6:137881282:G:A	C779Y	0.999
6:137881282:G:C	C779S	0.999
6:137881282:G:T	C779F	0.999
6:137881283:C:G	C779W	0.999
6:137881290:T:A	C782S	0.999
6:137881290:T:C	C782R	0.999
6:137881291:G:C	C782S	0.999
6:137871264:A:C	S13R	0.998
6:137871266:C:A	S13R	0.998

dbSNP variants (sampled 300 via entrez): RS1000492816 (6:137867395 C>A), RS1000802548 (6:137880956 G>C), RS1000823464 (6:137881686 G>C), RS1001041824 (6:137873811 T>C), RS1001166198 (6:137870439 C>A,T), RS1001410854 (6:137874215 G>A,T), RS1001552007 (6:137868810 C>T), RS1001646569 (6:137869194 T>C), RS1001717392 (6:137876937 C>T), RS1001807889 (6:137882600 T>C), RS1001839016 (6:137882180 G>A), RS1001914274 (6:137882144 T>A), RS1002015155 (6:137875579 A>T), RS1002083360 (6:137877497 C>T), RS1002112234 (6:137882926 G>A,T)

Disease associations

OMIM: gene MIM:191163 | disease phenotypes: MIM:616744

GenCC curated gene-disease

Disease	Classification	Inheritance
autoinflammatory syndrome, familial, Behcet-like 1	Strong	Autosomal dominant
hereditary pediatric Behçet-like disease	Moderate	Autosomal dominant
systemic lupus erythematosus	Supportive	Unknown

Mondo (5): autoinflammatory syndrome, familial, Behcet-like (MONDO:0031384), autoinflammatory syndrome, familial, Behcet-like 1 (MONDO:0800045), A20 haploinsufficiency (MONDO:0100222), (MONDO:0014761), systemic lupus erythematosus (MONDO:0007915)

Orphanet (2): Early-onset autoinflammatory syndrome due to A20 haploinsufficiency (Orphanet:674762), OBSOLETE: Hereditary pediatric Behçet-like disease (Orphanet:476102)

HPO phenotypes

57 total (30 of 57 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000093	Proteinuria
HP:0000155	Oral ulcer
HP:0000488	Retinopathy
HP:0000716	Depression
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000988	Skin rash
HP:0000992	Cutaneous photosensitivity
HP:0001250	Seizure
HP:0001369	Arthritis
HP:0001596	Alopecia
HP:0001824	Weight loss
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001882	Decreased total leukocyte count
HP:0001888	Decreased total lymphocyte count
HP:0001945	Fever
HP:0001954	Recurrent fever
HP:0002039	Anorexia
HP:0002072	Chorea
HP:0002583	Colitis
HP:0002716	Lymphadenopathy
HP:0003249	Genital ulcers
HP:0003453	Antineutrophil antibody positivity
HP:0003493	Antinuclear antibody positivity
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0005421	Decreased circulating complement C3 concentration
HP:0005764	Polyarticular arthritis

GWAS associations

69 associations (top):

Study	Trait	p-value
GCST000122_1	Rheumatoid arthritis	1.000000e-09
GCST000122_2	Rheumatoid arthritis	1.000000e-07
GCST000216_1	Systemic lupus erythematosus	3.000000e-12
GCST000322_8	Psoriasis	9.000000e-12
GCST000507_13	Systemic lupus erythematosus	1.000000e-17
GCST000612_19	Celiac disease	4.000000e-19
GCST000677_4	Rheumatoid arthritis	2.000000e-06
GCST000833_9	Psoriasis	7.000000e-07
GCST001725_90	Inflammatory bowel disease	1.000000e-21
GCST001776_15	Cardiac Troponin-T levels	8.000000e-06
GCST001795_23	Systemic lupus erythematosus	1.000000e-13
GCST002069_13	Systemic lupus erythematosus and Systemic sclerosis	2.000000e-09
GCST002217_3	Sjögren’s syndrome	8.000000e-09
GCST002318_103	Rheumatoid arthritis	2.000000e-29
GCST002318_124	Rheumatoid arthritis	2.000000e-20
GCST002318_125	Rheumatoid arthritis	7.000000e-11
GCST002323_5	Rheumatoid arthritis	3.000000e-08
GCST002738_17	Psoriasis	6.000000e-12
GCST002740_40	Inflammatory skin disease	9.000000e-16
GCST002740_76	Inflammatory skin disease	7.000000e-08
GCST002874_45	Psoriasis	5.000000e-10
GCST002874_9	Psoriasis	9.000000e-12
GCST003129_28	Primary biliary cholangitis	1.000000e-10
GCST003155_4	Systemic lupus erythematosus	2.000000e-31
GCST003156_38	Systemic lupus erythematosus	3.000000e-19
GCST003268_31	Psoriasis vulgaris	5.000000e-17
GCST003269_9	Cutaneous psoriasis	8.000000e-11
GCST003599_7	Systemic lupus erythematosus	2.000000e-14
GCST003620_5	Systemic lupus erythematosus or rheumatoid arthritis	2.000000e-19
GCST003622_32	Systemic lupus erythematosus	2.000000e-16

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005043	cardiac troponin T measurement
EFO:1001494	psoriasis vulgaris
EFO:0007773	cutaneous psoriasis measurement
EFO:0007924	tonsillectomy risk measurement
EFO:0010227	phosphatidylcholine ether measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008180	Lupus Erythematosus, Systemic	C17.300.480; C20.111.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523200 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

5 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs610604	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Arthritis;Psoriatic;Psoriasis
rs610604	Efficacy	4	ustekinumab	Psoriasis
rs6920220	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Arthritis;Psoriatic;Psoriasis
rs6920220	Efficacy	3	methotrexate
rs6927172	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Inflammatory Bowel Diseases;Ulcerative Colitis

PharmGKB variants

7 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs610604	TNFAIP3	3	2.00	2	ustekinumab;Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs6920220	SH3BP2, TNFAIP3	3	3.00	2	Tumor necrosis factor alpha (TNF-alpha) inhibitors;methotrexate
rs6927172	TNFAIP3	3	3.00	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs2230926	TNFAIP3		0.00	0
rs5029924	TNFAIP3		0.00	0
rs719149	TNFAIP3		0.00	0
rs3757173	TNFAIP3		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	increases expression, affects cotreatment, increases abundance	7
Lipopolysaccharides	increases secretion, affects cotreatment, increases activity, affects response to substance, increases degradation (+4 more)	5
Tetradecanoylphorbol Acetate	decreases reaction, increases expression, affects binding, increases reaction, decreases expression (+1 more)	5
nickel sulfate	increases expression	4
(+)-JQ1 compound	decreases expression	4
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression, decreases expression	4
Benzo(a)pyrene	increases expression, decreases expression	4
Silicon Dioxide	increases expression	4
Valproic Acid	increases expression, affects expression	4
Aflatoxin B1	affects expression, decreases methylation, increases expression	4
Asbestos, Crocidolite	affects expression, increases expression	4
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Cadmium	increases abundance, increases ubiquitination, increases expression	3
Cisplatin	affects cotreatment, affects expression, decreases expression, increases expression	3
Estradiol	increases expression	3
Zinc	increases reaction, decreases reaction, increases activity, increases expression, affects binding	3
Cyclosporine	decreases expression, increases expression	3
Magnetite Nanoparticles	affects cotreatment, increases expression	3
bisphenol A	increases expression, decreases expression	2
arsenite	affects binding, decreases reaction, increases expression	2
sulforaphane	decreases reaction, increases expression, decreases expression	2
ochratoxin A	increases expression, decreases expression, increases acetylation	2
cylindrospermopsin	increases expression	2
Temozolomide	increases expression, increases response to substance	2
Arsenic Trioxide	increases expression	2
Arsenic	decreases expression, affects cotreatment, increases abundance, increases expression	2
Benzene	decreases expression, increases expression	2
Cannabidiol	affects cotreatment, increases expression	2
Diethylhexyl Phthalate	decreases reaction, increases expression, affects reaction	2
Ozone	affects cotreatment, increases oxidation, increases abundance, increases expression	2

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4358857	Binding	Inhibition of A20 catalytic domain (unknown origin) assessed as reduction in cleavage of luminescent substrate Ub-AML at 100 uM	Re-Evaluating the Mechanism of Action of α,β-Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs. — J Med Chem

Cellosaurus cell lines

14 cell lines: 13 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0009	HDLM-2	Cancer cell line	Male
CVCL_1330	KM-H2	Cancer cell line	Male
CVCL_1361	L-428	Cancer cell line	Female
CVCL_2096	L-1236	Cancer cell line	Male
CVCL_2220	U-HO1	Cancer cell line	Male
CVCL_B1I6	Abcam A-549 TNFAIP3 KO 1	Cancer cell line	Male
CVCL_B2J0	Abcam HeLa TNFAIP3 KO	Cancer cell line	Female
CVCL_B2QQ	Abcam A-549 TNFAIP3 KO 2	Cancer cell line	Male
CVCL_D1UP	Abcam U-87MG TNFAIP3 KO	Cancer cell line	Male
CVCL_D8CP	Ubigene A-549 TNFAIP3 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00120887	PHASE4	COMPLETED	Lupus Atherosclerosis Prevention Study
NCT00125307	PHASE4	COMPLETED	Tacrolimus for the Treatment of Systemic Lupus Erythematosus With Membranous Nephritis
NCT00188188	PHASE4	UNKNOWN	Study of Endothelial Dysfunction in Systemic Lupus and Its Role in Heart Disease
NCT00371501	PHASE4	COMPLETED	Aspirin and Statins for Prevention of Atherosclerosis and Arterial Thromboembolism in Systemic Lupus Erythematosus
NCT00392093	PHASE4	COMPLETED	Effect of Hormone Replacement Therapy on Lupus Activity
NCT00413361	PHASE4	COMPLETED	The Reduction of Systemic Lupus Erythematosus Flares :Study PLUS
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00668330	PHASE4	COMPLETED	Steroid Induced Osteoporosis in Patients With Systemic Lupus Erythematosus
NCT00739050	PHASE4	TERMINATED	Effect of Simvastatin on Endothelial Function in Premenopausal Women With Systemic Lupus Erythematosus (0733-271)(TERMINATED)
NCT00815282	PHASE4	COMPLETED	Immune Response After Human Papillomavirus Vaccination in Patients With Autoimmune Disease
NCT00828178	PHASE4	COMPLETED	Efficacy of Fish Oil in Lupus Patients
NCT00866229	PHASE4	UNKNOWN	Efficacy and Adverse Effect of Simvastatin Compare to Rosuvastatin in Systemic Lupus Erythematosus (SLE) Patients With Corticosteroid Therapy and High Low-Density Lipoprotein (LDL) Cholesterol Level
NCT00911521	PHASE4	COMPLETED	Immunogenicity and Safety of a Quadrivalent Human Papillomavirus (HPV) Vaccine in Patients With SLE: a Controlled Study
NCT01101802	PHASE4	COMPLETED	Mycophenolate Mofetil in Systemic Lupus Erythematosus (MISSILE)
NCT01112215	PHASE4	COMPLETED	Enteric-coated Mycophenolate Sodium Versus Azathioprine for the Extra-renal Lupus Manifestations
NCT01151644	PHASE4	UNKNOWN	Safety and Efficacy of Anti-Pandemic H1N1 Vaccination in Rheumatic Diseases
NCT01276782	PHASE4	WITHDRAWN	Levothyroxine in Pregnant SLE Patients
NCT01322308	PHASE4	COMPLETED	Effect of Pioglitazone on Endothelial Function in Premenopausal Women With Uncomplicated Systemic Lupus Erythematosus
NCT01359826	PHASE4	WITHDRAWN	The Effect of Milnacipran on Fatigue and Quality of Life in Lupus Patients
NCT01597492	PHASE4	COMPLETED	A Study to Evaluate the Effect of Belimumab on Vaccine Responses in Subjects With Systemic Lupus Erythematosus (SLE)
NCT01632241	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in Black Race Patients With Systemic Lupus Erythematosus (SLE)
NCT01705977	PHASE4	COMPLETED	Belimumab Assessment of Safety in SLE
NCT01753401	PHASE4	COMPLETED	Acthar for the Treatment of Systemic Lupus Erythematosus (SLE) in Patients With a History of Persistently Active Disease
NCT02270970	PHASE4	UNKNOWN	Evaluation of Belimumab Impact on a BLyS Activity Signature Test in the Absence of Confounding Polypharmacy
NCT02477150	PHASE4	COMPLETED	Safety and Immunogenicity of a Zoster Vaccine in SLE
NCT02741960	PHASE4	COMPLETED	The Effect of Metformin on Reducing Lupus Flares
NCT02779153	PHASE4	WITHDRAWN	Acthar SLE (Systemic Lupus Erythematosus)
NCT02953821	PHASE4	COMPLETED	Acthar Gel for Active Systemic Lupus Erythematosus (SLE)
NCT03042260	PHASE4	UNKNOWN	Prophylactic Trimethoprim/Sulfamethoxazole to Prevent Severe Infections in Patients With Lupus Erythematous
NCT03098823	PHASE4	COMPLETED	A Crossover Study to Compare RAYOS to IR Prednisone to Improve Fatigue and Morning Symptoms for SLE
NCT03122431	PHASE4	COMPLETED	Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
NCT03543839	PHASE4	RECRUITING	Trial of Belimumab in Early Lupus
NCT04447053	PHASE4	UNKNOWN	Sequential Belimumab and T-cell Based Therapy in SLE
NCT04515719	PHASE4	COMPLETED	Efficacy and Safety of Belimumab in SLE Patients
NCT04893161	PHASE4	UNKNOWN	A Model About the Response of Belimumab in SLE
NCT04908865	PHASE4	COMPLETED	Open-label Study of Belimumab Plus Standard Therapy in Chinese Pediatric Participants With Active Systemic Lupus Erythematosus (SLE)
NCT04956484	PHASE4	COMPLETED	Belimumab In Early Systemic Lupus Erythematosus
NCT05559671	PHASE4	RECRUITING	Safety of the Herpes Zoster Subunit Vaccine in Lupus
NCT05666336	PHASE4	UNKNOWN	Multi-omics Studies on the Efficacy of Telitacicept in Chinese SLE Patients
NCT05748925	PHASE4	COMPLETED	Cardio Renal Effects of SGLT2 Inhibitors Among Lupus Nephritis Patients