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      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

      metabolism, Acetylmuramyl-Alanyl-Isoglutamine, pharmacology, Caco-2 Cells, Cell Membrane, drug effects, Crohn Disease, pathology, Enterocytes, HEK293 Cells, Humans, Models, Biological, Mutant Proteins, NF-kappa B, Nod2 Signaling Adaptor Protein, chemistry, Protein Binding, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Receptor-Interacting Protein Serine-Threonine Kinase 2, Reproducibility of Results, Signal Transduction, Substrate Specificity, Tight Junction Proteins

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          The intracellular nucleotide-binding oligomerization domain-2 (NOD2) receptor detects bacteria-derived muramyl dipeptide (MDP) and activates the transcription factor NF-κB. 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-κB 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.

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