TLE1 Modifies the Effects of NOD2 in the Pathogenesis of Crohn's Disease

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 141; no. 3; pp. 972 - 981.e2
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2011
• Subjects: Biopsy; Case-Control Studies; Co-Repressor Proteins; Colitis, Ulcerative - genetics; Colitis, Ulcerative - pathology; Colitis, Ulcerative - physiopathology; Colon - metabolism; Colon - pathology; Crohn Disease - genetics; Crohn Disease - pathology; Crohn Disease - physiopathology; Epistasis, Genetic - physiology; Gastroenterology and Hepatology; Genetic Analysis; Histone Acetyltransferases - genetics; Histone Acetyltransferases - metabolism; Humans; IBD Risk; Inflammation; Intestine; Lysine Acetyltransferase 5; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microarray Analysis; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mutation - genetics; N-Acetylgalactosaminyltransferases - genetics; N-Acetylgalactosaminyltransferases - metabolism; Nod2 Signaling Adaptor Protein - genetics; Nod2 Signaling Adaptor Protein - physiology; Polymorphism, Single Nucleotide - genetics; Polypeptide N-acetylgalactosaminyltransferase; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Repressor Proteins - genetics; Repressor Proteins - physiology; Signal Transduction - physiology; Vimentin - genetics; Vimentin - metabolism; transducin-like enhancer of split 1; yeast 2-hybrid; UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2; odds ratio; Genetic Analysis; GRIM1; NF-κB; SNP; TAK1; Intestine; PPP2R5E; Transforming growth factor-beta-activated kinase 1; single-nucleotide polymorphism; Gene associated with retinoic and interferon-induced mortality 19; IBD Risk; FIS1; fission 1 (mitochondrial outer membrane) homolog; OR; TLE1; GALNT2; CI; Inflammation; Y2H; nuclear factor-κB; HIV-1 Tat interactive protein; protein phosphatase 2, regulatory subunit B′, epsilon isoform; confidence interval; HTATIP
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2011.05.043

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).