MEKK4 sequesters RIP2 to dictate NOD2 signal specificity.
Curr Biol
; 18(18): 1402-8, 2008 Sep 23.
Article
em En
| MEDLINE
| ID: mdl-18775659
ABSTRACT
The Crohn's-disease-susceptibility protein, NOD2, coordinates signaling responses upon intracellular exposure to bacteria. Although NOD2 is known to activate NFkappaB, little is known about the molecular mechanisms by which NOD2 coordinates functionally separate signaling pathways such as NFkappaB, JNK, and p38 to regulate cytokine responses. Given that one of the characteristics of Crohn's disease is an altered cytokine response to normal bacterial flora, the coupling of signaling pathways could be important for Crohn's-disease pathophysiology. We find that a MAP3K, MEKK4, binds to RIP2 to sequester RIP2 from the NOD2 signaling pathway. This MEKK4RIP2 complex dissociates upon exposure to the NOD2 agonist, MDP, allowing NOD2 to bind to RIP2 and activate NFkappaB. MEKK4 thus sequesters RIP2 to inhibit the NOD2RIP2 complex from activating NFkappaB signaling pathways, and Crohn's-disease-associated NOD2 polymorphisms cannot compete with MEKK4 for RIP2 binding. Lastly, we find that MEKK4 helps dictate signal specificity downstream of NOD2 activation as knockdown of MEKK4 in macrophages exposed to MDP causes increased NFkappaB activity, absent p38 activity, and hyporesponsiveness to TLR2 and TLR4 agonists. These biochemical findings suggest that basal inhibition of the NOD2-driven NFkappaB pathway by MEKK4 could be important in the pathogenesis of Crohn's disease.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
MAP Quinase Quinase Quinase 4
/
Proteína Serina-Treonina Quinase 2 de Interação com Receptor
/
Proteína Adaptadora de Sinalização NOD2
Limite:
Humans
Idioma:
En
Revista:
Curr Biol
Assunto da revista:
BIOLOGIA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Estados Unidos