Small molecule inhibitors reveal an indispensable scaffolding role of RIPK2 in NOD2 signaling

• Matous Hrdinka ^[4] ; Lisa Schlicher ^[5] ; Bing Dai ^[1] ; Daniel M Pinkas ^[2] ; Joshua C Bufton ^[2] ; Sarah Picaud ^[2] ; Jennifer A Ward ^[2] ; Catherine Rogers ^[2] ; Chalada Suebsuwong ^[3] ; Sameer Nikhar ^[3] ; Gregory D Cuny ^[3] ; Kilian VM Huber ^[2] ; Panagis Filippakopoulos ^[2] ; Alex N Bullock ^[2] ; Alexei Degterev ^[1] ; Mads Gyrd‐Hansen ^[5]
  1. [1] Tufts University

     Tufts University

     City of Medford, Estados Unidos

     
  2. [2] University of Oxford

     University of Oxford

     Oxford District, Reino Unido

     
  3. [3] University of Houston

     University of Houston

     Estados Unidos

     
  4. [4] 1 Nuffield Department of Clinical Medicine Ludwig Institute for Cancer Research University of Oxford Oxford UK; 7Present address: Department of Haematooncology University Hospital Ostrava Ostrava‐Poruba Czech Republic
  5. [5] 1 Nuffield Department of Clinical Medicine Ludwig Institute for Cancer Research University of Oxford Oxford UK

  Mostrar afiliaciones +
• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 17, 2018
• Idioma: inglés
• Enlaces
  • Texto completo
• Resumen

  • RIPK2 mediates inflammatory signaling by the bacteria‐sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD‐mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP‐binding and XIAP‐mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between β2 and β3 of the N‐lobe of the kinase, which is in close proximity to the ATP‐binding pocket. Through characterization of a new series of ATP pocket‐binding RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2‐XIAP interaction, and of cellular and in vivo NOD2 signaling. Our study exemplifies how targeting of the ATP‐binding pocket in RIPK2 can be exploited to interfere with the RIPK2‐XIAP interaction for modulation of NOD signaling.