The sweet modification of Nod2, an innate immune receptor involved in Crohn's disease
Date
2017
Authors
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Publisher
University of Delaware
Abstract
The innate immune system, the first line of defense against pathogens, utilizes a series of receptors, including Toll-like receptors and Nod-like receptors, to generate the proper immune response. ☐ Nucleotide-binding oligomerization domain 2 (Nod2) is one of Nod-like receptors that can sense the bacterial peptidoglycan component, muramyl dipeptide (MDP). Upon activation Nod2 induces the production of various inflammatory molecules such as cytokines and chemokines. Genetic linkage analysis identified and revealed three major mutations in Nod2 associated with the development of Crohn’s disease are R702W, G908R, and 1007fs. In addition, previous studies have shown these Nod2 variants have lower NF-kB activation in response to MDP compared to wild type Nod2. ☐ The objective of this dissertation is to further characterize Nod2 and determine if it is post-translationally modified by O-GlcNAc. O-GlcNAcylation is one type of post-translational modification in which the O-GlcNAc transferase (OGT) transfers N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to selected serine and threonine residues of intracellular proteins. As GlcNAc is a major component of peptidoglycan of the bacterial cell wall and a large amount of GlcNAc is released from bacterial cell wall during cell wall remodeling, we hypothesized that Nod2 could be O-GlcNAcylated. ☐ We found that wild type Nod2 and Nod2 Crohn’s-associated variants are O- GlcNAcylated. This modification affects both wild type and Crohn’s mutant’s Nod2’s stability and ability to signal via the NF-κB pathway. ☐ Finally, in order to identify the peptidoglycan fragments that are generated inside the cellular environment, we have developed a new labelling approach to study peptidoglycan degradation process in vivo. Ultimately, we will utilize this approach to identify peptidoglycan fragments that effect the level of O-GlcNAcylation and OGT activity.
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Keywords
Pure sciences, Crohn's disease, NF-kB activity, Nod2, O-GlcNAcylation, Protein stability