Abstract
NOD2 contributes to the innate immune response and to the homeostasis of the intestinal mucosa. In response to its bacterial ligand, NOD2 interacts with RICK and activates the NF-κB and MAPK pathways, inducing gene transcription and synthesis of proteins required to initiate a balanced immune response. Mutations in NOD2 have been associated with an increased risk of Crohn’s Disease (CD), a disabling inflammatory bowel disease (IBD). Because NOD2 signaling plays a key role in CD, it is important to further characterize the network of protein interacting with NOD2. Using yeast two hybrid (Y2H) screens, we identified new NOD2 interacting proteins (NIP). The primary interaction was confirmed by coimmunoprecipitation and/or bioluminescence resonance energy transfer (BRET) experiments for 11 of these proteins (ANKHD1, CHMP5, SDCCAG3, TRIM41, LDOC1, PPP1R12C, DOCK7, VIM, KRT15, PPP2R3B, and C10Orf67). These proteins are involved in diverse functions, including endosomal sorting complexes required for transport (ESCRT), cytoskeletal architecture and signaling regulation. Additionally, we show that the interaction of 8 NIPs is compromised with the 3 main CD associated NOD2 mutants (R702W, G908R and 1007fs). Furthermore, to determine whether these NOD2 protein partners could be encoded by IBD susceptibility genes, a transmission disequilibrium test (TDT) was performed on 101 single nucleotide polymorphisms (SNPs) and the main corresponding haplotypes in genes coding for 15 NIPs using a set of 343 IBD families with 556 patients. Overall this work did not increase the number of IBD susceptibility genes but extends the NOD2 protein interaction network and suggests that NOD2 interactome and signaling depend upon the NOD2 mutation profile in CD.
Highlights
Toll Like Receptors (TLR) and Nod-Like Receptors (NLR) are major receptors of the innate immune system [1]
In order to identify new NOD2 interacting proteins, extensive Yeast 2-Hybrid (Y2H) screens were performed using a modified version of the Y2H system that reduces the rate of false positive clones [33, 36]
Other NOD2 interacting proteins (NIP) (ANKHD1/ SDCCAG3/TRIM41) do not interact at all with these Crohn’s Disease (CD) mutants. These results show that mutation targeting the C-terminus of NOD2 strongly altered its interaction with the NIPs isolated here and this indicates that the position of the mutation in NOD2 can affect NOD2 interactome
Summary
Toll Like Receptors (TLR) and Nod-Like Receptors (NLR) are major receptors of the innate immune system [1]. These phylogenetically conserved receptors are widely expressed in epithelial cells, as well as in antigen presenting cells, and they orchestrate the initial immune response toward micro-organisms. NOD2 induces autophagy, caspase activation, IL-1β secretion and modulates TLR2 signaling [3,4,5,6,7]. All of these functions are part of an efficient immune response, which is crucial for maintaining host homeostasis
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