TLE1 modifies the effects of NOD2 in the pathogenesis of Crohn's Disease

Nimmo, Elaine R.; Stevens, Craig; Phillips, Anne M.; Smith, Amanda; Drummond, Hazel E.; Noble, Colin L.; Quail, Michael; Davies, Gail; Aldhous, Marian C.; Wilson, David C.; Satsangi, Jack

Abstract

Background & Aims The mechanisms by which specific mutations in NOD2/CARD15 increase the risk for Crohn's disease (CD) are unclear. We identified proteins that interact with {NOD2} and investigated them by expression, genetic, and functional analyses. Methods By using a yeast 2-hybrid screen of an intestinal epithelial library, we identified proteins that interact with {NOD2} and confirmed the interactions in mammalian cells using co-immunoprecipitation. We used microarray analysis to analyze gene expression patterns in 302 intestinal biopsy samples (129 from patients with ulcerative colitis [UC], 106 with CD, and 67 controls). Eighty single-nucleotide polymorphisms within the genes that encoded 6 interacting proteins were genotyped in a discovery cohort (869 cases of inflammatory bowel disease [IBD], 885 controls) and a replication cohort (504 patients with IBD, 713 controls). We investigated interaction between transducin-like enhancer of split 1 (TLE1) and {NOD2} in {HEK293} cells. Results We identified 6 NOD2-interacting proteins (TLE1, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 [GALNT2], HIV-1 Tat interactive protein [HTATIP], Vimentin, fission 1 (mitochondrial outer membrane) homolog [FIS1], and protein phosphatase 2, regulatory subunit B′, epsilon isoform [PPP2R5E]). Of these, expression of {GALNT2} (CD, P = .004) and vimentin (CD, P = .006; UC, P = .0025) was altered in patients with {IBD} compared with controls. Single-nucleotide polymorphisms within {TLE1} were associated with susceptibility to CD, specifically with ileal disease (rs6559629, P = 3.1 × 10−5; odds ratio, 1.45). The {TLE1} risk allele is required for susceptibility to {CD} in carriers of {NOD2} mutations. In cells, {TLE1} and {NOD2} co-localized around the nuclear membrane and {TLE1} inhibited activation of nuclear factor-κB by NOD2. Conclusions Epistatic and biological interactions between {TLE1} and {NOD2} are involved in {IBD} pathogenesis. {NOD2} might be involved in a series of pathways such as epigenetic regulation of expression (via {TLE1} and HTATIP), biosynthesis of mucin (via GALNT2), apoptosis (via {PPP2R5E} and FIS1), and integrity of the intracellular cytoskeleton (vimentin).

Citation

Nimmo, E. R., Stevens, C., Phillips, A. M., Smith, A., Drummond, H. E., Noble, C. L., Quail, M., Davies, G., Aldhous, M. C., Wilson, D. C., & Satsangi, J. (2011). TLE1 modifies the effects of NOD2 in the pathogenesis of Crohn's Disease. Gastroenterology, 141(3), 972-981.e2. https://doi.org/10.1053/j.gastro.2011.05.043

• Journal Article Type: Article
• Acceptance Date: May 20, 2011
• Online Publication Date: May 27, 2011
• Publication Date: 2011-09
• Deposit Date: Jul 27, 2016
• Journal: Gastroenterology
• Print ISSN: 0016-5085
• Electronic ISSN: 1528-0012
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 141
• Issue: 3
• Pages: 972-981.e2
• DOI: https://doi.org/10.1053/j.gastro.2011.05.043
• Keywords: Gastroenterology
• Public URL: http://researchrepository.napier.ac.uk/Output/318062