Innate immune-directed NF-κB signaling requires site-specific NEMO ubiquitination.
Cell Rep
; 4(2): 352-61, 2013 Jul 25.
Article
em En
| MEDLINE
| ID: mdl-23871670
ABSTRACT
While the I kappa kinase (IKK) scaffolding protein NF-κB essential modulator (NEMO) binds to polyubiquitin chains to transmit inflammatory signals, NEMO itself is also ubiquitinated in response to a variety of inflammatory agonists. Although there have been hints that polyubiquitination of NEMO is essential for avoiding inflammatory disorders, the in vivo physiologic role of NEMO ubiquitination is unknown. In this work, we knock in a NEMO allele in which two major inflammatory agonist-induced ubiquitination sites cannot be ubiquitinated. We show that mice with a nonubiquitinatable NEMO allele display embryonic lethality. Heterozygous females develop inflammatory skin lesions, decreased B cell numbers, and hypercellular spleens. Embryonic lethality can be complemented by mating onto a TNFR1(-/-) background, at the cost of severe steatohepatitis and early mortality, and we also show that NEMO ubiquitination is required for optimal innate immune signaling responses. These findings suggest that NEMO ubiquitination is crucial for NF-κB activity in response to innate immune agonists.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
NF-kappa B
/
Peptídeos e Proteínas de Sinalização Intracelular
Limite:
Animals
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos