| The intermediate filament protein, vimentin, is a regulator of NOD2 activity. | |
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MedLine Citation:
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PMID: 22684479 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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ObjectiveMutations in the nucleotide-binding oligomerisation domain-containing protein 2 (NOD2) gene remain the strongest genetic determinants for Crohn's disease (CD). Having previously identified vimentin as a novel NOD2-interacting protein, the authors aimed to investigate the regulatory effects of vimentin on NOD2 function and the association of variants in Vim with CD susceptibility.DesignCoimmunoprecipitation, fluorescent microscopy and fractionation were used to confirm the interaction between NOD2 and vimentin. HEK293 cells stably expressing wild-type NOD2 or a NOD2 frameshift variant (L1007fs) and SW480 colonic epithelial cells were used alongside the vimentin inhibitor, withaferin A (WFA), to assess effects on NOD2 function using the nuclear factor-kappaB (NF-κB) reporter gene, green fluorescent protein-LC3-based autophagy, and bacterial gentamicin protection assays. International genome-wide association meta-analysis data were used to test for associations of single-nucleotide polymorphisms in Vim with CD susceptibility.ResultsThe leucine-rich repeat domain of NOD2 contained the elements required for vimentin binding; CD-associated polymorphisms disrupted this interaction. NOD2 and vimentin colocalised at the cell plasma membrane, and cytosolic mislocalisation of the L1007fs and R702W variants correlated with an inability to interact with vimentin. Use of WFA demonstrated that vimentin was required for NOD2-dependent NF-κB activation and muramyl dipeptide-induced autophagy induction, and that NOD2 and vimentin regulated the invasion and survival properties of a CD-associated adherent-invasive Escherichia coli strain. Genetic analysis revealed an association signal across the haplotype block containing Vim.ConclusionVimentin is an important regulator of NOD2 function and a potential novel therapeutic target in the treatment of CD. In addition, Vim is a candidate susceptibility gene for CD, supporting the functional data. |
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Authors:
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Craig Stevens; Paul Henderson; Elaine R Nimmo; Dinesh C Soares; Belgin Dogan; Kenneth W Simpson; Jeffrey C Barrett; ; David C Wilson; Jack Satsangi |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-6-8 |
Journal Detail:
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Title: Gut Volume: - ISSN: 1468-3288 ISO Abbreviation: - Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-6-11 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985108R Medline TA: Gut Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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