RNAi screening identifies mediators of NOD2 signaling: Implications for spatial specificity of MDP recognition

Lipinski, Simone, Grabe, Nils, Jacobs, Gunnar, Billmann-Born, Susanne, Till, Andreas, Hasler, Robert, Aden, Konrad, Paulsen, Maren, Arlt, Alexander, Kraemer, Lars, Hagemann, Nina, Erdmann, Kai Sven, Schreiber, Stefan and Rosenstiel, Philip (2012) RNAi screening identifies mediators of NOD2 signaling: Implications for spatial specificity of MDP recognition Proceedings of the National Academy of Sciences of the United States of America, 109 (52). pp. 21426-21431.

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Abstract

The intracellular nucleotide-binding oligomerization domain-2 (NOD2) receptor detects bacteria-derived muramyl dipeptide (MDP) and activates the transcription factor NF-kappa B. Here we describe the regulatome of NOD2 signaling using a systematic RNAi screen. Using three consecutive screens, we identified a set of 20 positive NF-kappa B regulators including the known pathway members RIPK2, RELA, and BIRC4 (XIAP) as well as FRMPD2 (FERM and PDZ domain-containing 2). FRMPD2 interacts with NOD2 via leucine-rich repeats and forms a complex with the membrane-associated protein ERBB2IP. We demonstrate that FRMPD2 spatially assembles the NOD2-signaling complex, hereby restricting NOD2-mediated immune responses to the basolateral compartment of polarized intestinal epithelial cells. We show that genetic truncation of the NOD2 leucine-rich repeat domain, which is associated with Crohn disease, impairs the interaction with FRMPD2, and that intestinal inflammation leads to down-regulation of FRMPD2. These results suggest a structural mechanism for how polarity of epithelial cells acts on intestinal NOD-like receptor signaling to mediate spatial specificity of bacterial recognition and control of immune responses.

Document Type: Article
Research affiliation: Kiel University
OceanRep > The Future Ocean - Cluster of Excellence
Kiel University > Kiel Marine Science
Refereed: Yes
ISSN: 0027-8424
Projects: Future Ocean
Date Deposited: 14 May 2014 09:50
Last Modified: 14 May 2014 09:50
URI: http://eprints.uni-kiel.de/id/eprint/24102

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