New signaling step for key player in Crohn’s Disease

This week, researchers report new findings that elucidate the role of NOD2, a key molecular player in Crohn’s Disease, in the cellular signaling pathways that control inflammatory responses. NOD2’s clinical relevance is clear from the fact that it is encoded by a Crohn’s Disease susceptibility gene. Understanding NOD2 has posed a particularly intriguing challenge for researchers because it appears able to somehow both activate and inhibit inflammatory cytokine responses in the cell. The work is reported by Lewis Cantley and colleagues at Harvard Medical School.

Crohn’s Disease is an autoimmune inflammatory disorder of the gastrointestinal tract and is histologically characterized by inflammation, epithelial ulceration, fissure formation, and stenosis of segments of the entire gastrointestinal tract. The disease leads to significant morbidity and is thought to result from an inappropriate immune response to bacteria that normally inhabit the gastrointestinal tract. Because Crohn’s Disease is characterized by too much initial acute inflammation, and, subsequently, too little subsequent negative regulation of that inflammatory response, pro-inflammatory and anti-inflammatory pathways appear to be faulty.

Previous work has shown that NOD2 acts as an intracellular receptor for bacteria and bacterial breakdown products, and because it appears capable of both activating and inhibiting inflammatory responses, NOD2 serves as a key integration point for the gastrointestinal tract’s response to infectious organisms. The biochemical nature of NOD2’s dichotomous role is unknown. In the new work, the researchers shed light on this problem by showing that NOD2 activation leads to the modification of NEMO, a central component of the NF-kB signaling pathway controlling inflammatory responses. NOD2 mutations responsible for Crohn’s Disease cause polymorphisms that prevent the NOD2 protein from properly modifying NEMO. These results suggest that this previously unrecognized modification on a component of the major inflammatory signaling pathway in the body helps to integrate inflammatory signals. These results also suggest that this signaling mechanism may ultimately represent a pharmacological target for the amelioration of Crohn’s Disease.

Derek W. Abbott, Andrew Wilkins, John M. Asara, and Lewis C. Cantley: “The Crohn’s Disease Gene, NOD2, Requires RIP2 in Order to Induce Ubiquitinylation of a Novel Site on NEMO”