TNFAIP3 (A20) Gene: Inflammation, NF-κB Regulation, and Disease Associations
Explore the TNFAIP3 gene, its protein product A20, and its critical role in immune regulation, inflammatory diseases, and cancer.
Gene Information Card
| Symbol | TNFAIP3 |
|---|---|
| Full Name | TNF Alpha Induced Protein 3 |
| Gene Type | Protein coding |
| Chromosomal Location | 6q23.3 |
| NCBI Gene ID | 7128 ncbi.nlm.nih.gov/gene/7128 |
| Ensembl ID | ENSG00000118503 |
| UniProt ID | P21580 |
| OMIM ID | 191163 |
| HGNC ID | 11896 |
| Aliases | A20, OTUD7C, TNFA1P2 |
Description
The TNFAIP3 gene encodes the zinc finger protein A20, a cytoplasmic ubiquitin-editing enzyme that negatively regulates NF-κB signaling and inflammation. A20 is induced by TNF and other inflammatory stimuli, and it functions as a deubiquitinase and E3 ligase to terminate NF-κB activation. Mutations and dysregulation of TNFAIP3 are linked to various inflammatory and autoimmune diseases, as well as certain cancers.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Rheumatoid Arthritis | Loss-of-function variants impair A20's inhibitory function, leading to enhanced NF-κB signaling and chronic inflammation. | ClinVar, OMIM |
| Systemic Lupus Erythematosus | TNFAIP3 polymorphisms are associated with increased susceptibility; reduced A20 expression contributes to aberrant immune activation. | ClinVar, OMIM |
| Psoriasis | Genetic variants in TNFAIP3 are associated with psoriasis risk, likely due to altered NF-κB regulation in skin cells. | ClinVar, OMIM |
| Crohn's Disease | TNFAIP3 variants may contribute to intestinal inflammation via dysregulated NF-κB responses. | ClinVar, OMIM |
| B-cell Lymphomas | Somatic mutations and deletions of TNFAIP3 are common in certain lymphomas, leading to constitutive NF-κB activation and tumor progression. | COSMIC, ClinVar |
| A20 Haploinsufficiency | Germline loss-of-function mutations cause autoinflammatory disease with features resembling Behçet's disease and inflammatory arthritis. | OMIM, ClinVar |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Whole Blood | 25.4 | High |
| Spleen | 18.2 | High |
| Lymph Node | 15.6 | High |
| Bone Marrow | 12.3 | Medium |
| Lung | 8.7 | Medium |
| Liver | 5.2 | Low |
| Brain | 2.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 45.2 | Cervical cancer cell line; high expression |
| K562 | 30.1 | Leukemia cell line; moderate expression |
| A549 | 22.8 | Lung carcinoma; moderate expression |
| MCF7 | 12.4 | Breast cancer; low expression |
| HepG2 | 8.9 | Liver cancer; low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| rs2230926 | SNP (missense) | ~10% in some populations | Associated with increased risk of autoimmune diseases; may affect A20 function. |
| c.406C>T (p.Arg136*) | Nonsense | Rare | Loss-of-function; causes A20 haploinsufficiency. |
| c.253A>G (p.Thr85Ala) | Missense | Rare | Impaired deubiquitinase activity; linked to autoinflammatory disease. |
| Deletion of 6q23.3 | Copy number loss | Somatic in lymphomas | Loss of A20 expression; promotes NF-κB activation. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in TNFAIP3 impair A20's ability to inhibit NF-κB, leading to excessive inflammation and autoimmunity. Examples include nonsense and frameshift mutations causing haploinsufficiency.
Gain of Function (GOF)
Gain-of-function mutations are rare and not well-characterized; some missense variants may enhance A20 activity, but their clinical significance is unclear.
Dominant Negative (DN)
Certain missense mutations may exert a dominant-negative effect by interfering with the wild-type A20 protein's function, though this is not fully established.
View complete mutation data：
Gene Ontology (GO)
| • cysteine-type deubiquitinase activity | • zinc ion binding |
| • ubiquitin protein ligase activity | • NF-kappaB binding |
| • signal transduction | • inflammatory response |
| • negative regulation of NF-kappaB transcription factor activity | • protein ubiquitination |
Pathways
• NF-kappaB signaling pathway
• TNF signaling pathway
• Toll-like receptor signaling pathway
• IL-1 signaling pathway
• Ubiquitin-mediated proteolysis
Protein Summary
The A20 protein is a 790-amino acid cytoplasmic protein with an N-terminal ovarian tumor (OTU) domain that has deubiquitinase activity and a C-terminal zinc finger domain with E3 ubiquitin ligase activity. A20 is induced by NF-κB and acts as a negative feedback regulator by removing K63-linked ubiquitin chains from signaling molecules like RIPK1 and TRAF6, and then adding K48-linked chains to target them for proteasomal degradation. This dual activity terminates NF-κB activation and prevents excessive inflammation.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TNFAIP3 Knockout HEK293 Cell Line | EDJ-KQ595 | Human | 7128 | Details Get a Quote |
| TNFAIP3 Knockout HeLa Cell Line | EDJ-KQ18184 | Human | 7128 | Details Get a Quote |
| TNFAIP3 Knockout A-549 Cell Line | EDJ-KQ19035 | Human | 7128 | Details Get a Quote |
| TNFAIP3 Knockout HCT 116 Cell Line | EDJ-KQ19036 | Human | 7128 | Details Get a Quote |
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