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TLE1 Modifies the Effects of NOD2 in the Pathogenesis of Crohn's Disease
- Source :
- Gastroenterology. 141:972-981.e2
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
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).
- Subjects :
- FIS1
Colon
Biopsy
Nod2 Signaling Adaptor Protein
Vimentin
Polymorphism, Single Nucleotide
Inflammatory bowel disease
Lysine Acetyltransferase 5
Mitochondrial Proteins
Pathogenesis
Crohn Disease
NOD2
Gene expression
medicine
Humans
Protein Phosphatase 2
Histone Acetyltransferases
Hepatology
biology
Microarray analysis techniques
Gastroenterology
Membrane Proteins
Epistasis, Genetic
Protein phosphatase 2
Microarray Analysis
medicine.disease
Molecular biology
digestive system diseases
Repressor Proteins
Case-Control Studies
Mutation
biology.protein
Cancer research
N-Acetylgalactosaminyltransferases
Colitis, Ulcerative
Co-Repressor Proteins
Signal Transduction
Subjects
Details
- ISSN :
- 00165085
- Volume :
- 141
- Database :
- OpenAIRE
- Journal :
- Gastroenterology
- Accession number :
- edsair.doi.dedup.....6e0eedc3bd2fe5924a4f5fcd6c7db4c8