{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFAIP3, which encodes the A20 protein, is a critical ubiquitin‐editing enzyme that safeguards cells from excessive inflammatory signaling. A20 achieves this by using two distinct functional domains: its N‐terminal deubiquitinase removes activating Lys63‐linked ubiquitin chains from key signaling molecules, while its C‐terminal zinc finger region acts as an E3 ubiquitin ligase that appends degradative Lys48‐linked chains to target proteins. Structural and biochemical studies have detailed how A20, sometimes in cooperation with interacting proteins such as ABIN-1, binds to components of the NF-κB signaling complex (for example, NEMO) and inhibits upstream kinase activity. In addition, A20 modulates antiviral as well as stress‐response pathways—for instance, by suppressing RIG-I–mediated IRF activation and inhibiting ASK1 activation in hepatocytes—to maintain cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies and genome-wide association analyses have consistently implicated variants and somatic lesions in TNFAIP3 with a broad range of autoimmune and inflammatory disorders. Altered A20 function has been associated with increased susceptibility to conditions such as psoriasis, systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. In patient cohorts and corresponding animal models, loss-of-function mutations or reduced expression of A20 result in unchecked NF-κB activation and chronic inflammatory responses, underscoring its essential role as a negative regulator of immune signaling. Furthermore, multiple fine-mapping and sequencing studies have defined risk haplotypes and rare coding mutations at the TNFAIP3 locus that correlate with disease onset and severity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in regulating inflammation, A20 also influences host responses to pathogens and tumor biology. In the context of infection, A20 is targeted by specific microRNAs to fine-tune macrophage and antiviral signaling—thereby modulating responses to bacterial (e.g. Mycobacterium tuberculosis) and viral challenges—and it suppresses overzealous activation of the antiviral state mediated by RIG-I. Moreover, deregulation of A20 contributes to cancer-related processes; for example, altered A20 expression can promote oncogenic survival in glioblastoma stem cells, enhance metastasis in basal-like breast cancers via modulation of the epithelial–mesenchymal transition regulator Snail1, and affect endothelial cell resistance to apoptosis. Further, adipokines such as adiponectin stimulate A20 expression in macrophages, emphasizing its broader significance in maintaining tissue homeostasis under stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yasuhiro Gon, Yasukiyo Asai, Shu Hashimoto, et al. 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