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Activation of the bacteria-sensing NOD receptors triggers inflammatory signalling via Receptor-interacting protein kinase 2 (RIPK2). Since RIPK2 inhibitors targeting the ATP-binding pocket have been shown to block this signalling pathway, it was assumed that RIPK2 kinase activity was important for signal transmission. In this work published recently in EMBO Journal, Hrdinka, Schlicher and colleagues from Mads Gyrd-Hansen’s lab demonstrate that kinase activity is in fact dispensable for NOD signalling and that these RIPK2 inhibitors are instead preventing the binding of the ubiquitin ligase, XIAP, and the subsequent XIAP-mediated ubiquitination of RIPK2 necessary for downstream signalling. This work could have therapeutic implications since NOD signalling is associated with several chronic inflammatory conditions such as Crohn’s disease.

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