Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inflammatory Signaling
Tatiana Goncharov 1, Stefanie Hedayati 1, Melinda M Mulvihill 2, Anita Izrael-Tomasevic 3, Kerry Zobel 1, Surinder Jeet 4, Anna V Fedorova 1, Celine Eidenschenk 2, Jason deVoss 4, Kebing Yu 3, Andrey S Shaw 5, Donald S Kirkpatrick 3, Wayne J Fairbrother 1, Kurt Deshayes 1, Domagoj Vucic 6

Inflammatory responses mediated by NOD2 depend on RIP2 kinase and ubiquitin ligase XIAP for that activation of nuclear factor |¨ºB (NF-|¨ºB), mitogen-activated protein kinases (MAPKs), and cytokine production. Herein, we show selective XIAP antagonism blocks NOD2-mediated inflammatory signaling and cytokine production by disturbing XIAP-RIP2 binding, which removes XIAP from the ubiquitination substrate RIP2. We establish the kinase activity of RIP2 is dispensable for NOD2 signaling. Rather, the conformation from the RIP2 kinase domain functions to manage binding towards the XIAP-BIR2 domain. Effective RIP2 kinase inhibitors block NOD2 signaling by disrupting RIP2-XIAP interaction. Finally, we identify NOD2 signaling and XIAP-dependent ubiquitination sites on RIP2 and reveal that mutating these lysine residues adversely affects NOD2 path signaling. Overall, these results reveal a vital role for that XIAP-RIP2 interaction in NOD2 inflammatory signaling and supply a molecular foundation for the style of innovative therapeutic strategies according to XIAP antagonists and RIP2 kinase inhibitors.GSK583