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Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
The nucleotide-binding domain and leucine-rich repeat containing protein NOD2 serves as a cytoplasmic pattern recognition molecule sensing bacterial muramyl dipeptide (MDP), whereas TLR2 mediates cell surface recognition of bacterial lipopeptides. In this study, we show that NOD2 stimulation activated Rac1 in human THP-1 cells and primary human monocytes. Rac1 inhibition or knock-down, or actin cytoskeleton disruption increased MDP-stimulated IL-8 secretion and NF-
B activation, whereas TLR2-dependent cell activation was suppressed by Rac1 inhibition. p21-activated kinase [Pak]-interacting exchange factor (β-PIX) plays a role in this negative regulation, because knock-down of β-PIX also led to increased NOD2-mediated but not TLR2-mediated IL-8 secretion, and coimmunoprecipitation experiments demonstrated that NOD2 interacted with β-PIX as well as Rac1 upon MDP stimulation. Moreover, knock-down of β-PIX or Rac1 abrogated membrane recruitment of NOD2, and interaction of NOD2 with its negative regulator Erbin. Overall, our data indicate that β-PIX and Rac1 mediate trafficking and negative regulation of NOD2-dependent signaling which is different from Rac1’s positive regulatory role in TLR2 signaling.
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 This work was supported in part by grants given by the Deutsche Forschungsgemeinschaft to M.K. and N.S. (Kr 2197/1-2), and B.O. (OP-86/5-1), by the Bundesministerium für Bildung und Forschung-funded network PROGRESS to S.H. and N.S. (B3), and by the Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin to B.O.
2 Address correspondence and reprint requests to Dr. Bastian Opitz, Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail address: bastian.opitz{at}charite.de
3 Abbreviations used in this paper: NLR, nucleotide-binding domain and leucine-rich repeat containing protein; CARD, caspase activation and recruitment domain; NOD, nucleotide-binding oligomerization domain; LRR, leucine rich repeat; MDP, muramyl dipeptide; RIP2, receptor interacting protein 2; β-PIX; p21-activated kinase [Pak]-interacting exchange factor; RNAi, RNA interference; siRNA, small interfering RNA.
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  S. Lipinski, A. Till, C. Sina, A. Arlt, H. Grasberger, S. Schreiber, and P. Rosenstiel DUOX2-derived reactive oxygen species are effectors of NOD2-mediated antibacterial responses J. Cell Sci., October 1, 2009; 122(19): 3522 - 3530. [Abstract] [Full Text] [PDF]
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