The NOD2-RICK complex signals from the plasma membrane.
NOD2 plays an important role in the innate immunity of the intestinal tract. By sensing the muramyl dipeptide (MDP), a bacterial wall component, NOD2 triggers the NF-kappaB signaling pathway and promotes the release of proinflammatory cytokines such as interleukin-8. Mutations in Nod2 (1007FS, R702W, G908R) impinge on NOD2 functions and are associated with the pathogenesis of Crohn disease, a chronic inflammatory bowel disease. Although NOD2 is usually described as a cytosolic receptor for MDP, the protein is also localized at the plasma membrane, and the 1007FS mutation delocalizes NOD2 to the cytoplasm (Barnich, N., Aguirre, J. E., Reinecker, H. C., Xavier, R., and Podolsky, D. K. (2005) J. Cell Biol. 170, 21-26; McDonald, C., Chen, F. F., Ollendorff, V., Ogura, Y., Marchetto, S., Lecine, P., Borg, J. P., and Nunez, G. (2005) J. Biol. Chem. 280, 40301-40309). In this study, we demonstrate that membrane-bound versions of NOD2 and Crohn disease-associated mutants R702W and G908R are capable of responding to MDP and activating the NF-kappaB pathway from this location. In contrast, the 1007FS mutant remains unable to respond to MDP from the plasma membrane. We also show that NOD2 promotes the membrane recruitment of RICK, a serine-threonine kinase involved in NF-kappaB activation downstream of NOD2. Furthermore, the artificial attachment of RICK at the plasma membrane provokes a constitutive and strong activation of the NF-kappaB pathway and secretion of interleukin-8 showing that optimal RICK activity depends upon its subcellular localization. Finally, we show that endogenous RICK localizes at the plasma membrane in the THP1 cell line. Thus, our data suggest that NOD2 is responsible for the membrane recruitment of RICK to induce a regulated NF-kappaB signaling and production of proinflammatory cytokines.
Lécine
Patrick
P
Centre de Recherche en Cancérologie de Marseille, UMR 599 INSERM-Institut Paoli-Calmettes-Universitédela Méditerranée, 27 Boulevard LeïRoure, 13009 Marseille, France.
Esmiol
Sophie
S
Métais
Jean-Yves
JY
Nicoletti
Cendrine
C
Nourry
Claire
C
McDonald
Christine
C
Nunez
Gabriel
G
Hugot
Jean-Pierre
JP
Borg
Jean-Paul
JP
Ollendorff
Vincent
V
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004285:Dogs; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016209:Interleukin-8 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
C508606:CXCL8 protein, human; D016209:Interleukin-8; D008565:Membrane Proteins; D016328:NF-kappa B; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2