NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2.
Department of Molecular Genetics and Microbiology; Department of Cancer Biology
Medical Subject Headings
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
Life Sciences | Medicine and Health Sciences
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.
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Citation: J Biol Chem. 2007 Dec 14;282(50):36223-9. Epub 2007 Oct 18. Link to article on publisher's website
The Journal of biological chemistry
Yang, Yibin; Yin, Catherine C.; Pandey, Amit K.; Abbott, Derek; Sassetti, Christopher M.; and Kelliher, Michelle A., "NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2." (2007). GSBS Student Publications. 1590.