A regulatory interface on RIPK2 is required for XIAP binding and NOD signaling activity

Signaling via the intracellular pathogen receptors Nucleotide-binding oligomerization domain-containing proteins NOD1 and NOD2 requires Receptor Interacting Kinase 2 (RIPK2), an adaptor kinase that can be targeted for the treatment of various inflammatory diseases. However, the molecular mechanisms of how RIPK2 contributes to NOD signaling are not completely understood. We generated FLAG-tagged RIPK2 knock-in mice using CRISPR/Cas9 technology to study NOD signaling mechanisms at the endogenous level. Using cells from these mice we were able to generate a detailed map of post-translational modifications on RIPK2 during NOD signaling and we identified a new regulatory interface on RIPK2, which dictates the crucial interaction with the E3 ligase XIAP.