Ubiquitination, innate immunity and inflammatory bowel disease are tightly linked. Dysregulation of ubiquitination pathways causes dysfunction of innate immune signaling which in turn, affects the mucosal immunity of the gastrointestinal tract. In the previous granting cycle, our lab has made important contributions in helping understand this process of dysregulation. Given this, in the next granting period, we will focus on an E3 ligase newly discovered to regulate the NOD:RIP2 signaling pathway. xIAP is a RING-domain containing E3 ubiquitin ligase. Its role in pediatric Crohn's disease was discovered when whole exome sequencing was performed on pediatric patients with severe, steroid-resistant IBD. A significant subset of these patients were found to have both truncating and missense xIAP mutations, and early work showed that patients with mutations in the BIR2 domain of xIAP had deficient NOD:RIP2 signaling. While this work is incredibly important, the published literature is incomplete and contains many inconsistencies. For instance, Crohn's disease-causing xIAP mutations are present throughout the gene and only the mutations in a small region of xIAP (the BIR2 domain) affect NOD:RIP2 signaling. Additionally, while NOD2 polymorphic patients are at an increased risk of developing Crohn's disease, the high level of NOD2 polymorphism in the population (approximately 9%) means that most Crohn's disease- associated NOD2 carriers have normal GI mucosal immunologic homeostasis. In contrast, xIAP mutation- carriers develop a severe form of inflammatory bowel disease before the age of 5 years old that is intractable to current treatments. Lastly, while NOD2 polymorphisms phenotypes are largely restricted to Crohn's disease, xIAP mutation carriers also develop X-linked lymphoproliferative syndrome, a serious life-threatening inflammatory response to cytomegalovirus exposure. For all these reasons, we hypothesize that defective NOD:RIP2 signaling is not the only pathway affected by xIAP mutation and by understanding the pathways affected, we can discover new targets for inflammatory bowel disease treatment. It will be important to characterize genotype:phenotype relationships of xIAP mutation carriers. It will be important to determine the ubiquitination patterns disrupted by xIAP mutations in innate immune and inflammatory signaling, and it will be crucial to determine if inhibition of WT xIAP will be efficacious in the treatment of inflammatory bowel disease.
Diseases such as Crohn's disease and Ulcerative Colitis occur in the setting of a dysregulated response to the bacteria that line the intestine. One of the key proteins designed to maintain a normal environment is called xIAP (x-linked inhibitor of apoptosis). In a proportion of inflammatory bowel disease patients, this protein is non- functional and causes severe intestinal inflammation that is difficult to treat. This grant application aims to determine how mutant forms of xIAP cause inflammatory abnormalities and to then use that knowledge to determine if xIAP-based treatment of disease is a viable option for these patients.
Showing the most recent 10 out of 90 publications
