NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2.
The Rip2 kinase contains a caspase recruitment domain and has been implicated in the activation of the transcriptional factor NF-kappaB downstream of Toll-like receptors, Nod-like receptors, and the T cell receptor. Although Rip2 has been linked to Nod signaling, how Nod-Rip2 proteins mediate NF-kappaB activation has remained unclear. We find ... Rip2 required for Nod2-mediated NF-kappaB activation and to a lesser extent mitogen-activated protein kinase activation. We demonstrate that Rip2 and IkappaB kinase-gamma become stably polyubiquitinated upon treatment of cells with the NOD2 ligand, muramyl dipeptide. We also demonstrate a requirement for the E2-conjugating enzyme Ubc13, the E3 ubiquitin ligase Traf6, and the ubiquitin-activated kinase Tak1 in Nod2-mediated NF-kappaB activation. Rip2 polyubiquitination is also stimulated when macrophages are infected with live Mycobacterium tuberculosis but not when infected with heat-killed bacteria. Consistent with our data linking Rip2 to NOD and not Toll-like receptor signaling, M. tuberculosis-induced Rip2 polyubiquitination appears MyD88-independent. Collectively, these data reveal that the NOD2 pathway is ubiquitin-regulated and that Rip2 employs a ubiquitin-dependent mechanism to achieve NF-kappaB activation.
Mesh Terms:
Acetylmuramyl-Alanyl-Isoglutamine, Adjuvants, Immunologic, Animals, Cells, Cultured, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, I-kappa B Kinase, MAP Kinase Kinase Kinases, Macrophages, Mice, Mice, Knockout, Mycobacterium tuberculosis, Myeloid Differentiation Factor 88, NF-kappa B, Nod2 Signaling Adaptor Protein, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Tuberculosis, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination
Acetylmuramyl-Alanyl-Isoglutamine, Adjuvants, Immunologic, Animals, Cells, Cultured, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, I-kappa B Kinase, MAP Kinase Kinase Kinases, Macrophages, Mice, Mice, Knockout, Mycobacterium tuberculosis, Myeloid Differentiation Factor 88, NF-kappa B, Nod2 Signaling Adaptor Protein, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Tuberculosis, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination
J. Biol. Chem.
Date: Dec. 14, 2007
PubMed ID: 17947236
View in: Pubmed Google Scholar
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