NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2

Yibin Yang, Catherine Yin, Amit Pandey, Derek Abbott, Christopher Sassetti, Michelle A. Kelliher

Research output: Contribution to journalArticlepeer-review

194 Scopus citations

Abstract

The Rip2 kinase contains a caspase recruitment domain and has been implicated in the activation of the transcriptional factor NF-κB 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-κB activation has remained unclear. We find Rip2 required for Nod2-mediated NF-κB activation and to a lesser extent mitogen-activated protein kinase activation. We demonstrate that Rip2 and IκB kinase-γ 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-κB 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-κB activation.

Original languageEnglish
Pages (from-to)36223-36229
Number of pages7
JournalJournal of Biological Chemistry
Volume282
Issue number50
DOIs
StatePublished - Dec 14 2007

Fingerprint

Dive into the research topics of 'NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2'. Together they form a unique fingerprint.

Cite this