Inflammatory bowel diseases (IBD) are chronic conditions characterized by inflammation of the gastrointestinal tract. IBD patients suffer from increased intestinal epithelial cell (IEC) apoptosis and exhibit a hyperactivated NF-kB pathway leading to immune system activation and proinflammatory cytokine production. Recent studies have indicated that linear ubiquitination is a key regulatory mechanism of NF-κB signalling and cell death. Genome-wide association studies in IBD patients revealed polymorphisms in a specific E2 ubiquitin- conjugating enzyme that plays a role in linear ubiquitination. We hypothesize that linear ubiquitination could be involved in both NF-kB hyperactivation and IEC death during normal gut homeostasis and intestinal inflammation. To investigate the physiological function and mechanism of action of linear ubiquitination in IECs, we will generate IEC-specific knock-out and transgenic mice for this specific enzyme. These mice will be carefully phenotyped for the development of intestinal disease, both spontaneous and in a mouse colitis model. In addition, the mechanism of action will be studied in more detail intestinal organoids derived from these mice.