{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:39:12Z","timestamp":1791225552274,"version":"4.1.0"},"reference-count":45,"publisher":"BMJ","issue":"8","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Gut"],"accepted":{"date-parts":[[2013,8,23]]},"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD:\n                      <jats:italic>CYLD<\/jats:italic>\n                      ,\n                      <jats:italic>USP40<\/jats:italic>\n                      ,\n                      <jats:italic>APEH<\/jats:italic>\n                      and\n                      <jats:italic>USP3. CYLD<\/jats:italic>\n                      was the most significant gene with the intronically located rs12324931 the strongest associated SNP (p\n                      <jats:sub>FDR<\/jats:sub>\n                      =1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC:\n                      <jats:italic>USP40<\/jats:italic>\n                      ,\n                      <jats:italic>APEH<\/jats:italic>\n                      ,\n                      <jats:italic>DAG1<\/jats:italic>\n                      and\n                      <jats:italic>USP3. CYLD<\/jats:italic>\n                      , 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\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      (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-\u03baB regulator CYLD. This resulted in I\u03baB-\u03b1 degradation and NF-\u03baB activation. This activity was very important for the pathogenicity of AIEC since decreased\n                      <jats:italic>CYLD<\/jats:italic>\n                      resulted in increased ability of AIEC LF82 to replicate intracellularly.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/gutjnl-2012-303205","type":"journal-article","created":{"date-parts":[[2013,10,3]],"date-time":"2013-10-03T22:32:18Z","timestamp":1380839538000},"page":"1265-1274","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":93,"title":["Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease"],"prefix":"10.1136","volume":"63","author":[{"given":"Isabelle","family":"Cleynen","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Vazeille","sequence":"additional","affiliation":[{"name":"Clermont Universit\u00e9, Inserm U1071, Universit\u00e9 d'Auvergne, INRA USC 2018, Clermont-Ferrand, France"},{"name":"Centre Hospitalier Universitaire, Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Artieda","sequence":"additional","affiliation":[{"name":"Progenika Biopharma, S.A., Derio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hein W","family":"Verspaget","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"Dutch Initiative on Crohn and Colitis (ICC)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Szczypiorska","sequence":"additional","affiliation":[{"name":"Progenika Biopharma, S.A., Derio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Agn\u00e8s","family":"Bringer","sequence":"additional","affiliation":[{"name":"Clermont Universit\u00e9, Inserm U1071, Universit\u00e9 d'Auvergne, INRA USC 2018, Clermont-Ferrand, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L","family":"Lakatos","sequence":"additional","affiliation":[{"name":"1st Department of Medicine, Semmelweis University, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Seibold","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Spitalnetz Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirstie","family":"Parnell","sequence":"additional","affiliation":[{"name":"Peninsula Medical School, University of Exeter & Plymouth, Exeter, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinse K","family":"Weersma","sequence":"additional","affiliation":[{"name":"Dutch Initiative on Crohn and Colitis (ICC)"},{"name":"Department of Gastroenterology and Hepatology, University Medical Center Groningen and the University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jestinah M","family":"Mahachie John","sequence":"additional","affiliation":[{"name":"Systems and Modeling Unit, Montefiore Institute, University of Li\u00e8ge, Li\u00e8ge, Belgium"},{"name":"Bioinformatics and Modeling, GIGA-R, University of Li\u00e8ge, Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Morgan-Walsh","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of medicine, University of Southampton, Southampton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominiek","family":"Staelens","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Arijs","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert","family":"De Hertogh","sequence":"additional","affiliation":[{"name":"Department of Morphology and Molecular Pathology, University Hospital Gasthuisberg, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Clinical Research, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atilla","family":"Tordai","sequence":"additional","affiliation":[{"name":"Hungarian National Blood Transfusion Service, Molecular Diagnostics, Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel W","family":"Hommes","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"Dutch Initiative on Crohn and Colitis (ICC)"},{"name":"Division of Digestive Diseases, Inflammatory Bowel Diseases Center, UCLA, Los Angeles, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tariq","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Peninsula Medical School, University of Exeter & Plymouth, Exeter, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cisca","family":"Wijmenga","sequence":"additional","affiliation":[{"name":"Dutch Initiative on Crohn and Colitis (ICC)"},{"name":"Department of Genetics, University Medical Center Groningen and the University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Pender","sequence":"additional","affiliation":[{"name":"Clinical and Experimental Sciences, Faculty of medicine, University of Southampton, Southampton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Rutgeerts","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristel","family":"Van Steen","sequence":"additional","affiliation":[{"name":"Systems and 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