# Aberrant Ubiquitination Networks in Genetic Crohn's Disease

> **NIH NIH P01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $396,250

## Abstract

PROJECT SUMMARY
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.

## Key facts

- **NIH application ID:** 9995025
- **Project number:** 5P01DK091222-10
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Derek W Abbott
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2011-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995025

## Citation

> US National Institutes of Health, RePORTER application 9995025, Aberrant Ubiquitination Networks in Genetic Crohn's Disease (5P01DK091222-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9995025. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*