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J. Biol. Chem., Vol. 282, Issue 50, 36223-36229, December 14, 2007

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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, and Michelle A. Kelliher¹

From the Department of Pathology, Case Western University School of Medicine, Cleveland, Ohio 44106 and the Departments of Molecular Genetics and Microbiology and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

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

Received for publication, April 12, 2007 , and in revised form, October 3, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605. E-mail: michelle.kelliher{at}umassmed.edu.

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