Abstract
The NF-κB transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-κB is achieved by K63-linked polyubiquitination of key signaling molecules which recruit kinase complexes that in turn activate the IκB kinase (IKK). Ubiquitination is a highly dynamic process and is balanced by deubiquitinases that cleave polyubiquitin chains and terminate downstream signaling events. The A20 deubiquitinase is a critical negative regulator of NF-κB and inflammation, since A20-deficient mice develop uncontrolled and spontaneous multi-organ inflammation. Furthermore, specific polymorphisms in the A20 genomic locus predispose humans to autoimmune disease. Recent studies also indicate that A20 is an important tumor suppressor that is inactivated in B-cell lymphomas. Therefore, targeting A20 may form the basis of novel therapies for autoimmune disease and lymphomas.
Publication types
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Research Support, N.I.H., Extramural
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Review
MeSH terms
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Animals
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Autoimmune Diseases / genetics*
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Autoimmune Diseases / immunology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / immunology*
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Humans
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I-kappa B Kinase / immunology
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Immunity, Innate / genetics
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology*
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Lymphoma, B-Cell / genetics*
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Lymphoma, B-Cell / immunology
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Lymphoma, B-Cell / pathology
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Mice
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Mice, Knockout
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NF-kappa B / immunology
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Nuclear Proteins / genetics
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Nuclear Proteins / immunology*
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Signal Transduction / immunology
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Tumor Necrosis Factor alpha-Induced Protein 3
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Tumor Suppressor Proteins / immunology*
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Ubiquitin-Protein Ligases / immunology*
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Ubiquitination / immunology
Substances
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Nuclear Proteins
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Tumor Suppressor Proteins
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Ubiquitin-Protein Ligases
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I-kappa B Kinase
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3