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RNAi screening identifies mediators of NOD2 signaling: Implications for spatial specificity of MDP recognition
- Source :
- Proceedings of the National Academy of Sciences. 109:21426-21431
- Publication Year :
- 2012
- Publisher :
- Proceedings of the National Academy of Sciences, 2012.
-
Abstract
- 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.
- Subjects :
- Multidisciplinary
HEK 293 cells
PDZ domain
Nod2 Signaling Adaptor Protein
Biological Sciences
Biology
digestive system diseases
XIAP
Cell biology
chemistry.chemical_compound
chemistry
RNA interference
NOD2
Humans
RNA Interference
Signal transduction
Acetylmuramyl-Alanyl-Isoglutamine
Transcription factor
Muramyl dipeptide
Signal Transduction
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 109
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....c267ccaf8ac038b2a0b2e9531f95997d