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

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.

Source: EMBO Journal - September 3, 2018 Category: Molecular Biology Authors: Hrdinka, M., Schlicher, L., Dai, B., Pinkas, D. M., Bufton, J. C., Picaud, S., Ward, J. A., Rogers, C., Suebsuwong, C., Nikhar, S., Cuny, G. D., Huber, K. V., Filippakopoulos, P., Bullock, A. N., Degterev, A., Gyrd-Hansen, M. Tags: Autophagy & Cell Death, Immunology Articles Source Type: research