Direct, noncatalytic mechanism of IKK inhibition by A20.
Mol Cell
; 44(4): 559-71, 2011 Nov 18.
Article
en En
| MEDLINE
| ID: mdl-22099304
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteínas Nucleares
/
Transducción de Señal
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FN-kappa B
/
Dedos de Zinc
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Péptidos y Proteínas de Señalización Intracelular
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Quinasa I-kappa B
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Inflamación
Límite:
Humans
Idioma:
En
Revista:
Mol Cell
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos