Inflammatory bowel diseases are characterized by chronic, uncontrolled inflammation in the intestine. IBD is a major health problem as the patients usually require lifelong treatments. NF-κB family of transcription factors are master regulators of the inflammatory signaling pathway, and they control the expression of several inflammatory genes. It is common for IBD to have a dysregulated NF-κB pathway, leading to uncontrolled activation of NF-κB. The underlying mechanism of regulation of the inflammatory NF-κB pathway is still elusive. This project aims to understand the regulation of NF-κB pathway in the gut by a recently discovered type of ubiquitin chains called M1-linked ubiquitin (M1-Ub) chains. The NF-κB pathway activity is tightly regulated by ubiquitin signaling, as E3 ligases target ubiquitin chains to important mediators of the pathway. Recently, we showed that uncontrolled induction of M1-Ub chains drives intestinal inflammation in Drosophila. We have now found that DREDD, a caspase-8 homologue in the fly, is subjected to M1-ubiquitination. Caspases have been extensively studied for their role in apoptosis, but they are also involved in other important functions such as regulation of NF-κB pathway. How caspases are activated during inflammation, simultaneously switching-off its apoptotic function is not fully understood. We aim to understand how M1-ubiquitination affects the function of DREDD, and consequently the activation of NF-κB during intestinal inflammation.

2015