TNFAIP3 (tumor necrosis factor, alpha-induced protein 3)

2009-06-01   Silvia Rasi , Davide Rossi , Gianluca Gaidano 

Division of Hematology, Department of Clinical, Experimental Medicine & Center of Biotechnologies for Applied Medical Research, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy


Atlas Image
A. Chromosomal location of TNFAIP3 gene.
B. Mapping of TNFAIP3 gene and local order on genomic context of the chromosome 6.


Atlas Image
Exon-intron structure of the TNFAIP3 gene. Blue boxes correspond to protein coding regions, while white boxes correspond to non coding regions.


TNFAIP3 is a functioning gene of 15869 bp comprising 9 exons and 8 introns. Exon 1, the 5 part of exon 2 and the 3 part of exon 9 are non coding.


Length of the transcript is 4446 bp.
Coding sequence: CDS 67-2439.
mRNA is expressed at high levels in lymph nodes, respiratory tract, larynx, trachea and kidney.


Atlas Image
Representation of the TNFAIP3 protein with localization of recognized domains. The ovarian tumor domain (OTU) is shown in green, while the seven zinc finger structures (ZNF A20) are shown in blue (UniProtKB/Swiss-Prot entry P21580).


Protein length of the unprocessed precursor: 790 amino acids.
Molecular weight of the unprocessed precursor: 89614 Da.
TNFAIP3 is a zinc finger protein containing seven A20-type finger motifs (E3 ubiquitin ligase domain) in its C-terminal region and a deubiquitinating enzyme domain, termed ovarian tumor (OTU) domain, in its N-terminal region. TNFAIP3 belongs to the peptidase C64 family. It is a homodimer that interacts with:
-TNIP1 (TNFAIP3 interacting protein 1, also known as Naf1 or ABIN-1),
-TAX1BP1 (Tax1 binding protein 1, also known as TXBP151 or T6BP),
-ITCH (itchy E3 ubiquitin protein ligase homolog (mouse)),
-RNF11 (ring finger protein 11),
-TRAF1, TRAF2, TRAF6 (TNF receptor-associated factor 1, 2 and 6).


Expression of TNFAIP3 is induced by TNF and is repressed by PML (promyelocytic leukemia) protein.


Cytoplasm and nucleus.


TNFAIP3 inhibits activation of NFKB and AP-1 transcription factors, and TNF- and IL-1beta (interleukin-1beta)- induced apoptosis.
TNFAIP3 is critical for limiting inflammatory processes by terminating TNF-induced NFKB responses, and contributes to the in vivo effects of TNF.
TNFAIP3 also restricts NFKB signaling in response to stimulation of TLR (toll-like receptor) and NOD (nuclear-binding and oligomerization domain) pathways.
TNFAIP3 possesses dual ubiquitin-editing functions. In particular, the N-terminal domain of TNFAIP3 is a deubiquitinating enzyme (DUB) for Lys63-linked polyubiquitinated signaling mediators such as TRAF2/6 and RIP1 (receptor interacting protein 1). Instead, the C-terminal domain of TNFAIP3 is a ubiquitin ligase (E3) for Lys48-linked degradative polyubiquitination of the same substrates. TNFAIP3 has a specificity for particular polyubiquitinated substrates to regulate NFKB activation in the TNF, IL-1beta and TLR pathways.
TNFAIP3 has a role in the function of the lymphoid system because it inhibits NFKB signaling and may play an important role in lymphomagenesis. TNFAIP3 also negatively regulates the activity of CARD10 (caspase recruitment domain family, member 10) and BCL10 (B-cell CLL/lymphoma 10) in lymphoid and non-lymphoid cells.
A TNFAIP3-mediated inhibition of TNF-induced apoptosis is associated with the inhibition of caspase-8.
TNFAIP3 acts forming a multiprotein complex with other proteins, in particular ABIN-1, TAX1BP1, ITCH, RNF11, TRAF1, TRAF2, TRAF6, to regulate NFKB signaling cascade and TNF-induced cell death.
TNFAIP3 negatively regulates the maturation, inflammatory cytokine production and immunostimulatory potency of dendritic cells.


Interspecies: ortholog to murine TNFAIP3 and homolog to Caenorhabditis elegans F21C3.2.



Deletions and bi-allelic somatic mutations involving TNFAIP3 gene have been identified in different subtypes of B-cell lymphomas. Most of the TNFAIP3 mutations are nonsense or frameshift that prevent production of full-length TNFAIP3 protein.

Implicated in

The incidence of MZBCL in the Western world is approximately 10% of all non-Hodgkins lymphomas (NHLs). MZBCL includes three distinct clinicopathological forms:
1- Extranodal MZBCL of mucosa-associated lymphoid tissue (MALT) type,
3- Nodal MZBCL.
The TNFAIP3 gene, that is a common genetic target in B-cell lymphomas, is frequently inactivated by somatic mutations and/or deletions in MALT lymphoma. Homozygous deletions of the chromosomal band 6q23, involving the TNFAIP3 gene, were identified in ocular adnexal MZBCLs. Inactivating mutations encoding truncated TNFAIP3 protein were also identified in extranodal, nodal and splenic MZBCLs.
The patients usually have prolonged survival, but some cases may feature an aggressive disease. In ocular adnexal MZBCLs, TNFAIP3 deletion appears to be associated with adverse clinical parameters and with concurrent involvement of different adnexal tissues or extraocular sites at diagnosis. TNFAIP3 deletion is also associated with a higher proportion of relapse and with a shorter relapse-free survival.
TNFAIP3 inactivation by somatic mutation and/or deletion represents a genetic aberration across all MZBCL subtypes, which may contribute to lymphomagenesis by inducing constitutive NFKB activation. This suggests that TNFAIP3 may act as a tumor suppressor gene in MZBCLs.
cHL is a disease that involves a clonal expansion of neoplastic B lymphocytes. A constitutive NFKB activity has been detected in cHL and somatic mutations have been identified in the TNFAIP3 gene. Both TNFAIP3 alleles are inactivated, with frequent chromosomal deletion of TNFAIP3. Reconstitution of wild-type protein in TNFAIP3-deficient cHL cell lines results in a downregulation of NFKB activity and in suppression of cell growth with induction of apoptosis. In fact TNFAIP3-deficient cells generate tumours in immunodeficient mice, whereas the re-expression of TNFAIP3 suppresses the tumorigenicity.
TNFAIP3 has been identified in cHL, as in other B-cell lymphomas, as a tumor suppressor gene. Loss of TNFAIP3 function, inducing a constitutive activity of NFKB, is probably involved in the pathogenesis of cHL.
DLBCL is the most common type of lymphoma in adulthood and is a heterogeneous disease, with patients exhibiting a wide range of clinical variables, outcomes and responses to therapy. In fact DLBCL includes different biologically and clinically distinct subtypes:
- Activated B-cell-like (ABC) DLBCL.
ABC-DLBCL, that is the most aggressive subtype, is associated with constitutive activation of NFKB. ABC-DLBCL and a smaller fraction of GCB-DLBCL carry somatic mutations in TNFAIP3 gene. In fact, approximately 30% of patients display biallelic inactivation of TNFAIP3 by mutations and/or deletions. Reconstitution of TNFAIP3 induces apoptosis and cell growth arrest, indicating a tumour suppressor role of the gene.
NFKB activation in DLBCL is caused by genetic lesions affecting multiple genes, including TNFAIP3. Alterations of these genes may promote lymphomagenesis by leading to abnormally prolonged NFKB responses.
PMBL is a subtype of DLBCL defined by a combination of clinical and pathologic features. PMBL typically presents in young female patients, that have bulky mediastinal masses with frequent invasion of adjacent structures. PMBL is a lymphoma with constitutive NFKB activity and significantly high frequency of TNFAIP3 mutations.
TNFAIP3 has been identified as a tumor suppressor gene in PMBL by showing frequent somatic and clonal biallelic inactivation of the gene. Loss of TNFAIP3 function contributes to the constitutive activity of the transcription factor NFKB and the survival and/or proliferation of the cells.
Entity name
Breast cancer
Breast cancer is the most common cancer among women in developed countries. The etiology is multifactorial and the majority of these tumors express estrogen receptor (ER). Tamoxifen has been shown to be an effective adjiuvant therapy for ER+ tumors, but only 60% of ER+ tumors respond to this therapy. TNFAIP3 is overexpressed in breast cancer cells and confers resistance to tamoxifen-induced cytotoxicity.
TNFAPI3 represents a potential prognostic marker of breast cancer, because an increased expression of TNFAIP3 is associated with an aggressive phenotype of the disease.
TNFAIP3 is probably a key protein involved in tamoxifen resistance in breast cancer because it is overexpressed in tamoxifen-resistant cell lines. It is a possible target for developing new strategies to prevent drug resistance in breast cancer.
Entity name
Nasopharyngeal carcinoma (NPC)
TNFAIP3 expression is correlated with the differentiation stages of NPC. In particular, TNFAIP3 expression contributes to the development of undifferentiated NPC as well as poorly differentiated head and neck squamous cell carcinomas (SCCs).
TNFAIP3 may have a role in the pathogenesis and aggressiveness of these tumors, probably because TNFAIP3 is implicated in survival pathways.


Pubmed IDLast YearTitleAuthors
110079522000A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis.Beyaert R et al
187078982008Roles of ubiquitination in pattern-recognition receptors and type I interferon receptor signaling.Bibeau-Poirier A et al
153340862004The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses.Boone DL et al
190061942009A20 deletion is associated with copy number gain at the TNFA/B/C locus and occurs preferentially in translocation-negative MALT lymphoma of the ocular adnexa and salivary glands.Chanudet E et al
160562672005Ubiquitin signalling in the NF-kappaB pathway.Chen ZJ et al
103981201999A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinoma.Codd JD et al
194121642009Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.Compagno M et al
86634991996A20 blocks endothelial cell activation through a NF-kappaB-dependent mechanism.Cooper JT et al
161158772005Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation.Cusson-Hermance N et al
104356311999The zinc finger protein A20 interacts with a novel anti-apoptotic protein which is cleaved by specific caspases.De Valck D et al
24062431990Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin.Dixit VM et al
147486872004Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity.Evans PC et al
105236111999A20 inhibits cytokine-induced apoptosis and nuclear factor kappaB-dependent gene activation in islets.Grey ST et al
156533172005A20 inhibits NF-kappaB activation by dual ubiquitin-editing functions.Heyninck K et al
183420092008The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals.Hitotsumatsu O et al
178862472008TNFAIP3 is the target gene of chromosome band 6q23.3-q24.1 loss in ocular adnexal marginal zone B cell lymphoma.Honma K et al
85579941996A20 zinc finger protein inhibits TNF and IL-1 signaling.Jäättelä M et al
194121632009Frequent inactivation of A20 in B-cell lymphomas.Kato M et al
113196092001A20 zinc finger protein inhibits TNF-induced apoptosis and stress response early in the signaling cascades and independently of binding to TRAF2 or 14-3-3 proteins.Lademann U et al
110094212000Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice.Lee EG et al
163060432006Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20.Lin R et al
181643162008Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20.Lin SC et al
193806362009A20 takes on tumors: tumor suppression by an ubiquitin-editing enzyme.Malynn BA et al
150647602004RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation.Meylan E et al
192585982009The NF-{kappa}B negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas.Novak U et al
16187491992The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity.Opipari AW Jr et al
156619102005A20 is a negative regulator of IFN regulatory factor 3 signaling.Saitoh T et al
193806392009TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma.Schmitz R et al
182460702008The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20.Shembade N et al
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182975242008Characterization of 6q deletions in mature B cell lymphomas and childhood acute lymphoblastic leukemia.Thelander EF et al
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Other Information

Locus ID:

NCBI: 7128
MIM: 191163
HGNC: 11896
Ensembl: ENSG00000118503


dbSNP: 7128
ClinVar: 7128
TCGA: ENSG00000118503


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
NF-kappa B signaling pathwayKEGGhsa04064
NF-kappa B signaling pathwayKEGGko04064
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathwaysREACTOMER-HSA-168643
NOD1/2 Signaling PathwayREACTOMER-HSA-168638
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathwaysREACTOMER-HSA-168928
Negative regulators of RIG-I/MDA5 signalingREACTOMER-HSA-936440
Signal TransductionREACTOMER-HSA-162582
Death Receptor SignallingREACTOMER-HSA-73887
TNF signalingREACTOMER-HSA-75893
TNFR1-induced proapoptotic signalingREACTOMER-HSA-5357786
TNFR1-induced NFkappaB signaling pathwayREACTOMER-HSA-5357956
Regulation of TNFR1 signalingREACTOMER-HSA-5357905
Ovarian tumor domain proteasesREACTOMER-HSA-5689896
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164713366Tumor necrosis factor alpha (TNF-alpha) inhibitorsChemicalClinicalAnnotationassociatedPD24776844, 30653751
PA166048654ustekinumabChemicalClinicalAnnotationassociatedPD23521149, 27564082
PA443750Colitis, UlcerativeDiseaseClinicalAnnotationassociatedPD24776844
PA445451PsoriasisDiseaseClinicalAnnotationassociatedPD23521149, 27564082, 30653751
PA446116Inflammatory Bowel DiseasesDiseaseClinicalAnnotationassociatedPD24776844
PA446198Arthritis, PsoriaticDiseaseClinicalAnnotationassociatedPD30653751


Pubmed IDYearTitleCitations
152585972004De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.632
191692542009Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.410
198381932009Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus.332
179824562007Two independent alleles at 6q23 associated with risk of rheumatoid arthritis.231
191659182008Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus.225
191659182008Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus.225
187948532008Common variants at CD40 and other loci confer risk of rheumatoid arthritis.199
194121632009Frequent inactivation of A20 in B-cell lymphomas.184
191659192008Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.173
191659192008Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.173


Silvia Rasi ; Davide Rossi ; Gianluca Gaidano

TNFAIP3 (tumor necrosis factor, alpha-induced protein 3)

Atlas Genet Cytogenet Oncol Haematol. 2009-06-01

Online version: