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
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.
DOI of Published Version
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 Y, Yin CC, Pandey AK, Abbott D, Sassetti CM, Kelliher MA. (2007). NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2.. GSBS Student Publications. https://doi.org/10.1074/jbc.M703079200. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/1590