Notably, one-fifth of patients with XIAP deficiency develop severe CD-like granulomatous colitis.17–20 More recently, the ubiquitin (Ub) ligase XIAP emerged as an essential signal transducer downstream of the cytosolic sensor NOD2.21, 22 Following activation of NOD2 by muramyl dipeptide (MDP), a bacterial cell wall product, XIAP binds and ubiquitinates the adapter protein receptor-interacting kinase 2 (RIPK2) to facilitate nuclear factor (NF)-κB signalling and cytokine production.23 Multiple Ub-dependent signalling events regulate NOD2 activity and converge on the adapter protein RIPK2.24, 25. This evidence concerns the gene RIPK2 and Cowden disease.