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Nat Commun. 2018 Oct 2;9(1):4043. doi: 10.1038/s41467-018-06451-3.

RIP2 filament formation is required for NOD2 dependent NF-κB signalling.

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European Molecular Biology Laboratory, 71 Avenue des Martyrs, CS 90181, 38042, Grenoble, Cedex 9, France.
Univ. Grenoble Alpes, CNRS, CEA, CNRS, IBS, F-38000, Grenoble, France.
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Department for NMR-supported Structural, Biology Robert-Rössle-Straße 10, 13125, Berlin, Germany.
University Grenoble Alpes, CEA, CNRS, IBS, F-38000, Grenoble, France.
Grasilda Zenkeviciute, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, United Kingdom.
European Molecular Biology Laboratory, Structural and Computational Biology Unit, Meyerhofstraße 1, 69117, Heidelberg, Germany.
European Molecular Biology Laboratory, 71 Avenue des Martyrs, CS 90181, 38042, Grenoble, Cedex 9, France.


Activation of the innate immune pattern recognition receptor NOD2 by the bacterial muramyl-dipeptide peptidoglycan fragment triggers recruitment of the downstream adaptor kinase RIP2, eventually leading to NF-κB activation and proinflammatory cytokine production. Here we show that full-length RIP2 can form long filaments mediated by its caspase recruitment domain (CARD), in common with other innate immune adaptor proteins. We further show that the NOD2 tandem CARDs bind to one end of the RIP2 CARD filament, suggesting a mechanism for polar filament nucleation by activated NOD2. We combine X-ray crystallography, solid-state NMR and high-resolution cryo-electron microscopy to determine the atomic structure of the helical RIP2 CARD filament, which reveals the intermolecular interactions that stabilize the assembly. Using structure-guided mutagenesis, we demonstrate the importance of RIP2 polymerization for the activation of NF-κB signalling by NOD2. Our results could be of use to develop new pharmacological strategies to treat inflammatory diseases characterised by aberrant NOD2 signalling.

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