title: Direct, noncatalytic mechanism of IKK inhibition by A20.
abstract: A20 is a potent anti-inflammatory protein that inhibits NF-κB, and A20 dysfunction is associated with autoimmunity and B cell lymphoma. A20 harbors a deubiquitination enzyme domain and can employ multiple mechanisms to antagonize ubiquitination upstream of NEMO, a regulatory subunit of the IκB kinase complex (IKK). However, direct evidence of IKK inhibition by A20 is lacking, and the inhibitory mechanism remains poorly understood. Here we show that A20 can directly impair IKK activation without deubiquitination or impairment of ubiquitination enzymes. We find that polyubiquitin binding by A20, which is largely dependent on A20's seventh zinc-finger motif (ZnF7), induces specific binding to NEMO. Remarkably, this ubiquitin-induced recruitment of A20 to NEMO is sufficient to block IKK phosphorylation by its upstream kinase TAK1. Our results suggest a noncatalytic mechanism of IKK inhibition by A20 and a means by which polyubiquitin chains can specify a signaling outcome.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Skaug
authors.forename: Jueqi
authors.initials: J
authors.lastname: Chen
authors.forename: Fenghe
authors.initials: F
authors.lastname: Du
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.forename: Averil
authors.initials: A
authors.lastname: Ma
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D015551:Autoimmunity / Q000235:genetics; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000235:genetics; D015870:Gene Expression; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D025821:Polyubiquitin; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D054875:Ubiquitination; D016335:Zinc Fingers / Q000235:genetics*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D009687:Nuclear Proteins; D025821:Polyubiquitin; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D000099151:MAP Kinase Kinase Kinase 7; C076529:TNFAIP3 protein, human
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