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

Matous Hrdinka, Lisa Schlicher, Bing Dai, Daniel M. Pinkas, Joshua C. Bufton, Sarah Picaud, Jennifer A. Ward, Catherine Rogers, Chalada Suebsuwong, Sameer Nikhar, Gregory D. Cuny, Kilian V.M. Huber, Panagis Filippakopoulos, Alex N. Bullock, Alexei Degterev*, Mads Gyrd-Hansen

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

24 Citations (Scopus)
323 Downloads (Pure)

Abstract

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 vivoNOD2 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.

Original languageEnglish
Article numbere99372
Number of pages16
JournalEMBO Journal
Volume37
Issue number17
Early online date19 Jul 2018
DOIs
Publication statusPublished - 3 Sep 2018

Keywords

  • kinase inhibitor
  • NOD2 signaling
  • RIPK2
  • ubiquitin
  • XIAP

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