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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.

Pubmed ID: 17947236

Authors

  • Yang Y
  • Yin C
  • Pandey A
  • Abbott D
  • Sassetti C
  • Kelliher MA

Journal

The Journal of biological chemistry

Publication Data

December 14, 2007

Associated Grants

None

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