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TLE1 modifies the effects of NOD2 in the pathogenesis of Crohn's disease
Elaine R Nimmo1, Craig Stevens, Anne M Phillips
1Gastrointestinal Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK. enimmo@ed.ac.uk
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).
Insights
Specific mutations in NOD2 increase Crohn's disease risk. Researchers found that transducin-like enhancer of split 1 (TLE1) interacts with NOD2, influencing disease susceptibility and nuclear factor-kappaB activation.
Area of Science:
- Gastroenterology and Immunology
- Molecular Biology
- Genetics
Background:
- The precise mechanisms linking NOD2/CARD15 mutations to Crohn's disease (CD) susceptibility remain incompletely understood.
- Identifying interacting proteins of NOD2 is crucial for elucidating its role in CD pathogenesis.
Purpose of the Study:
- To identify proteins interacting with NOD2 using a yeast 2-hybrid screen.
- To investigate the expression, genetic associations, and functional roles of these interacting proteins in inflammatory bowel disease (IBD).
Main Methods:
- Yeast 2-hybrid screening and co-immunoprecipitation were used to identify and confirm NOD2-interacting proteins.
- Microarray analysis of intestinal biopsies assessed gene expression patterns in patients with ulcerative colitis (UC), CD, and controls.
- Genotyping of single-nucleotide polymorphisms (SNPs) in interacting protein genes was performed in discovery and replication cohorts.
Main Results:
- Six NOD2-interacting proteins were identified, including transducin-like enhancer of split 1 (TLE1), GALNT2, HTATIP, Vimentin, FIS1, and PPP2R5E.
- Expression of GALNT2 and vimentin was significantly altered in patients with IBD.
- SNPs in TLE1 were associated with CD susceptibility, particularly ileal disease, and were required for CD susceptibility in NOD2 mutation carriers.
Conclusions:
- Epistatic and biological interactions between TLE1 and NOD2 play a role in IBD pathogenesis.
- NOD2 is implicated in multiple pathways, including epigenetic regulation (TLE1, HTATIP), mucin biosynthesis (GALNT2), apoptosis (PPP2R5E, FIS1), and cytoskeleton integrity (vimentin).
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