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

Erika Pellegrini, Ambroise Desfosses, Arndt Wallmann, Wiebke Manuela Schulze, Kristina Rehbein, Philippe Mas, Luca Signor, Stephanie Gaudon, Grasilda Zenkeviciute, Michael Hons, Helene Malet, Irina Gutsche, Carsten Sachse, Guy Schoehn, Hartmut Oschkinat and Stephen Cusack ()
Additional contact information
Erika Pellegrini: European Molecular Biology Laboratory
Ambroise Desfosses: Univ. Grenoble Alpes, CNRS, CEA, CNRS, IBS
Arndt Wallmann: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Department for NMR-supported Structural
Wiebke Manuela Schulze: European Molecular Biology Laboratory
Kristina Rehbein: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Department for NMR-supported Structural
Philippe Mas: Univ. Grenoble Alpes, CNRS, CEA, CNRS, IBS
Luca Signor: University Grenoble Alpes, CEA, CNRS, IBS
Stephanie Gaudon: European Molecular Biology Laboratory
Grasilda Zenkeviciute: European Molecular Biology Laboratory
Michael Hons: European Molecular Biology Laboratory
Helene Malet: Univ. Grenoble Alpes, CNRS, CEA, CNRS, IBS
Irina Gutsche: Univ. Grenoble Alpes, CNRS, CEA, CNRS, IBS
Carsten Sachse: European Molecular Biology Laboratory, Structural and Computational Biology Unit
Guy Schoehn: Univ. Grenoble Alpes, CNRS, CEA, CNRS, IBS
Hartmut Oschkinat: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Department for NMR-supported Structural
Stephen Cusack: European Molecular Biology Laboratory

Nature Communications, 2018, vol. 9, issue 1, 1-19

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06451-3

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