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

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

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

Identity

HGNC

TNFAIP3

LOCATION

6q23.3

IMAGE

LEGEND

A. Chromosomal location of TNFAIP3 gene.

LEGEND

B. Mapping of TNFAIP3 gene and local order on genomic context of the chromosome 6.

LOCUSID

7128

ALIAS

A20,AISBL,OTUD7C,TNFA1P2

FUSION GENES

Show Gene Fusions

DNA/RNA

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

Description

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.

Transcription

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.

Proteins

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).

Description

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

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

Localisation

Cytoplasm and nucleus.

Function

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.

Homology

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

Mutations

Somatic

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

Entity name

Marginal Zone B-cell Lymphoma (MZBCL)

Disease

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.

Prognosis

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.

Oncogenesis

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.

Entity name

Classical Hodgkins Lymphoma (cHL)

Disease

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.

Oncogenesis

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.

Entity name

Diffuse Large B-cell Lymphoma (DLBCL)

Disease

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.

Oncogenesis

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.

Entity name

Primary Mediastinal B-cell Lymphoma (PMBL)

Disease

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.

Oncogenesis

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

Disease

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.

Prognosis

TNFAPI3 represents a potential prognostic marker of breast cancer, because an increased expression of TNFAIP3 is associated with an aggressive phenotype of the disease.

Oncogenesis

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)

Disease

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).

Oncogenesis

TNFAIP3 may have a role in the pathogenesis and aggressiveness of these tumors, probably because TNFAIP3 is implicated in survival pathways.

Bibliography

Pubmed ID	Last Year	Title	Authors
11007952	2000	A20 and A20-binding proteins as cellular inhibitors of nuclear factor-kappa B-dependent gene expression and apoptosis.	Beyaert R et al
18707898	2008	Roles of ubiquitination in pattern-recognition receptors and type I interferon receptor signaling.	Bibeau-Poirier A et al
15334086	2004	The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses.	Boone DL et al
19006194	2009	A20 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
16056267	2005	Ubiquitin signalling in the NF-kappaB pathway.	Chen ZJ et al
10398120	1999	A20 RNA expression is associated with undifferentiated nasopharyngeal carcinoma and poorly differentiated head and neck squamous cell carcinoma.	Codd JD et al
19412164	2009	Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma.	Compagno M et al
8663499	1996	A20 blocks endothelial cell activation through a NF-kappaB-dependent mechanism.	Cooper JT et al
16115877	2005	Rip1 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
10435631	1999	The zinc finger protein A20 interacts with a novel anti-apoptotic protein which is cleaved by specific caspases.	De Valck D et al
2406243	1990	Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin.	Dixit VM et al
14748687	2004	Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity.	Evans PC et al
10523611	1999	A20 inhibits cytokine-induced apoptosis and nuclear factor kappaB-dependent gene activation in islets.	Grey ST et al
15653317	2005	A20 inhibits NF-kappaB activation by dual ubiquitin-editing functions.	Heyninck K et al
18342009	2008	The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals.	Hitotsumatsu O et al
17886247	2008	TNFAIP3 is the target gene of chromosome band 6q23.3-q24.1 loss in ocular adnexal marginal zone B cell lymphoma.	Honma K et al
8557994	1996	A20 zinc finger protein inhibits TNF and IL-1 signaling.	Jäättelä M et al
19412163	2009	Frequent inactivation of A20 in B-cell lymphomas.	Kato M et al
11319609	2001	A20 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
11009421	2000	Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice.	Lee EG et al
16306043	2006	Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20.	Lin R et al
18164316	2008	Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20.	Lin SC et al
19380636	2009	A20 takes on tumors: tumor suppression by an ubiquitin-editing enzyme.	Malynn BA et al
15064760	2004	RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation.	Meylan E et al
19258598	2009	The NF-{kappa}B negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas.	Novak U et al
1618749	1992	The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity.	Opipari AW Jr et al
15661910	2005	A20 is a negative regulator of IFN regulatory factor 3 signaling.	Saitoh T et al
19380639	2009	TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma.	Schmitz R et al
18246070	2008	The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20.	Shembade N et al
8692885	1996	The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation.	Song HY et al
18311150	2008	A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell-mediated suppression.	Song XT et al
9468507	1998	Bcl-xL functions downstream of caspase-8 to inhibit Fas- and tumor necrosis factor receptor 1-induced apoptosis of MCF7 breast carcinoma cells.	Srinivasan A et al
18349075	2008	A20 is a negative regulator of BCL10- and CARMA3-mediated activation of NF-kappaB.	Stilo R et al
18297524	2008	Characterization of 6q deletions in mature B cell lymphomas and childhood acute lymphoblastic leukemia.	Thelander EF et al
17297453	2007	A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells.	Vendrell JA et al
15474016	2004	A20 is a potent inhibitor of TLR3- and Sendai virus-induced activation of NF-kappaB and ISRE and IFN-beta promoter.	Wang YY et al
15258597	2004	De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.	Wertz IE et al

Other Information

Locus ID:

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

Variants:

dbSNP: 7128
ClinVar: 7128
TCGA: ENSG00000118503
COSMIC: TNFAIP3

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000118503	ENST00000237289	P21580
ENSG00000118503	ENST00000420009	Q5VXQ8
ENSG00000118503	ENST00000421450	Q5VXR0
ENSG00000118503	ENST00000433680	Q5VXQ9
ENSG00000118503	ENST00000612899	P21580
ENSG00000118503	ENST00000614035	A0A087WXL5
ENSG00000118503	ENST00000615468	A0A087WVN3
ENSG00000118503	ENST00000619035	A0A087WU80
ENSG00000118503	ENST00000620204	D3TTY5
ENSG00000118503	ENST00000621150	A0A087X1N1

Expression (GTEx)

100

150

200

250

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
NOD-like receptor signaling pathway	KEGG	ko04621
NOD-like receptor signaling pathway	KEGG	hsa04621
Measles	KEGG	ko05162
Measles	KEGG	hsa05162
Epstein-Barr virus infection	KEGG	hsa05169
Epstein-Barr virus infection	KEGG	ko05169
NF-kappa B signaling pathway	KEGG	hsa04064
NF-kappa B signaling pathway	KEGG	ko04064
TNF signaling pathway	KEGG	hsa04668
TNF signaling pathway	KEGG	ko04668
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Immune System	REACTOME	R-HSA-168256
Innate Immune System	REACTOME	R-HSA-168249
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	REACTOME	R-HSA-168643
NOD1/2 Signaling Pathway	REACTOME	R-HSA-168638
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways	REACTOME	R-HSA-168928
Negative regulators of RIG-I/MDA5 signaling	REACTOME	R-HSA-936440
Signal Transduction	REACTOME	R-HSA-162582
Death Receptor Signalling	REACTOME	R-HSA-73887
TNF signaling	REACTOME	R-HSA-75893
TNFR1-induced proapoptotic signaling	REACTOME	R-HSA-5357786
TNFR1-induced NFkappaB signaling pathway	REACTOME	R-HSA-5357956
Regulation of TNFR1 signaling	REACTOME	R-HSA-5357905
Deubiquitination	REACTOME	R-HSA-5688426
Ovarian tumor domain proteases	REACTOME	R-HSA-5689896
IL-17 signaling pathway	KEGG	ko04657
IL-17 signaling pathway	KEGG	hsa04657

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PD	PMIDs
PA164713366	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Chemical	ClinicalAnnotation	associated	PD	24776844, 30653751
PA166048654	ustekinumab	Chemical	ClinicalAnnotation	associated	PD	23521149, 27564082
PA443750	Colitis, Ulcerative	Disease	ClinicalAnnotation	associated	PD	24776844
PA445451	Psoriasis	Disease	ClinicalAnnotation	associated	PD	23521149, 27564082, 30653751
PA446116	Inflammatory Bowel Diseases	Disease	ClinicalAnnotation	associated	PD	24776844
PA446198	Arthritis, Psoriatic	Disease	ClinicalAnnotation	associated	PD	30653751
PA450428	methotrexate	Chemical	ClinicalAnnotation	associated	PD	20921970

References

Pubmed ID	Year	Title	Citations
15258597	2004	De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.	632
19169254	2009	Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.	410
19838193	2009	Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus.	332
17982456	2007	Two independent alleles at 6q23 associated with risk of rheumatoid arthritis.	231
19165918	2008	Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus.	225
19165918	2008	Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus.	225
18794853	2008	Common variants at CD40 and other loci confer risk of rheumatoid arthritis.	199
19412163	2009	Frequent inactivation of A20 in B-cell lymphomas.	184
19165919	2008	Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.	173
19165919	2008	Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.	173

Citation

Silvia Rasi ; Davide Rossi ; Gianluca Gaidano

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

Atlas Genet Cytogenet Oncol Haematol. 2009-06-01

Online version: http://atlasgeneticsoncology.org/gene/42600/tnfaip3