TY - JOUR
T1 - NOD2 pathway activation by MDP or Mycobacterium tuberculosis infection involves the stable polyubiquitination of Rip2
AU - Yang, Yibin
AU - Yin, Catherine
AU - Pandey, Amit
AU - Abbott, Derek
AU - Sassetti, Christopher
AU - Kelliher, Michelle A.
PY - 2007/12/14
Y1 - 2007/12/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=37548999003&partnerID=8YFLogxK
U2 - 10.1074/jbc.M703079200
DO - 10.1074/jbc.M703079200
M3 - Article
C2 - 17947236
AN - SCOPUS:37548999003
SN - 0021-9258
VL - 282
SP - 36223
EP - 36229
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 50
ER -