دورية أكاديمية
Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease
| العنوان: | Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease |
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| المؤلفون: | Cleynen, Isabelle, Vazeille, Emilie, Artieda, Marta, Verspaget, Hein W., Szczypiorska, Magdalena, Bringer, Marie-Agnès, Lakatos, Peter L., Seibold, Frank, Parnell, Kirstie, Weersma, Rinse K., John, Jestinah M. Mahachie, Morgan-Walsh, Rebecca, Staelens, Dominiek, Arijs, Ingrid, de Hertogh, Gert, Mueller, Stefan, Tordai, Atilla, Hommes, Daniel W., Ahmad, Tariq, Wijmenga, Cisca, Pender, Sylvia, Rutgeerts, Paul, van Steen, Kristel, Lottaz, Daniel, Vermeire, Séverine, Darfeuille-Michaud, Arlette |
| المساهمون: | Department of Clinical and Experimental Medicine, Translational Research in GastroIntestinal Disorders, Université Catholique de Louvain = Catholic University of Louvain (UCL), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA), Progenika Biopharma, Dutch Initiative on Crohn and Colitis (ICC), Department of Gastroenterology and Hepatology, Leiden University Medical Center (LUMC), Universiteit Leiden = Leiden University -Universiteit Leiden = Leiden University, 1st Department of Medicine, Semmelweis University Budapest, Department of Gastroenterolog, Spital Netz Bern, Peninsula Medical School, University of Exeter-Plymouth University, University Medical Center Groningen Groningen (UMCG), Montefiore Institute, Systems and Modeling Unit - GIGA-R, Bioinformatics and Modeling, Université de Liège, Faculty of medicine, Clinical and Experimental Sciences, University of Southampton, Department of Morphology and Molecular Pathology, University Hospital Gasthuisberg Leuven, Department of Clinical Research, Universität Bern / University of Bern (UNIBE), Molecular Diagnostics, Hungarian National Blood Transfusion Service, Inflammatory Bowel Diseases Center, Division of Digestive Diseases, University of California Los Angeles (UCLA), University of California (UC)-University of California (UC), Department of Genetics, Department of Rheumatology, Clinical Immunology and Allergology, CHU Clermont-Ferrand, European Community's Seventh Framework Programme (FP7) 200931, Centre Hospitalier Universitaire de Clermont-Ferrand, Association Francois Aupetit |
| المصدر: | ISSN: 0017-5749. |
| بيانات النشر: | HAL CCSD BMJ Publishing Group |
| سنة النشر: | 2014 |
| المجموعة: | HAL Clermont Auvergne (Université Blaise Pascal Clermont-Ferrand / Université d'Auvergne) |
| مصطلحات موضوعية: | nf-kappa-b, escherichia-coli strains, crohns-disease, negative regulator, ileal mucosa, cyld, invasion, susceptibility, activation, cancer, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology |
| الوصف: | Objective: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up. [br/]Design: We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis. [br/]Results: Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (p(FDR)=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-kappa B regulator CYLD. This resulted in I kappa B-alpha degradation and NF-kappa B activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly. [br/]Conclusions: Our results reveal the UPS, and CYLD specifically, as an important ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/24092863; hal-01223556; https://hal.science/hal-01223556Test; PRODINRA: 281878; PUBMED: 24092863; WOS: 000339164200012 |
| DOI: | 10.1136/gutjnl-2012-303205 |
| الإتاحة: | https://doi.org/10.1136/gutjnl-2012-303205Test https://hal.science/hal-01223556Test |
| رقم الانضمام: | edsbas.51031312 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1136/gutjnl-2012-303205 |
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