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Original article
Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease
  1. Isabelle Cleynen1,
  2. Emilie Vazeille2,3,
  3. Marta Artieda4,
  4. Hein W Verspaget5,6,
  5. Magdalena Szczypiorska4,
  6. Marie-Agnès Bringer2,
  7. Peter L Lakatos7,
  8. Frank Seibold8,
  9. Kirstie Parnell9,
  10. Rinse K Weersma6,10,
  11. Jestinah M Mahachie John11,12,
  12. Rebecca Morgan-Walsh13,
  13. Dominiek Staelens1,
  14. Ingrid Arijs1,
  15. Gert De Hertogh14,
  16. Stefan Müller15,
  17. Atilla Tordai16,
  18. Daniel W Hommes5,6,17,
  19. Tariq Ahmad9,
  20. Cisca Wijmenga6,18,
  21. Sylvia Pender13,
  22. Paul Rutgeerts1,
  23. Kristel Van Steen11,12,
  24. Daniel Lottaz19,
  25. Severine Vermeire1,
  26. Arlette Darfeuille-Michaud2,3
  1. 1Department of Clinical and Experimental Medicine, TARGID, KU Leuven, Leuven, Belgium
  2. 2Clermont Université, Inserm U1071, Université d'Auvergne, INRA USC 2018, Clermont-Ferrand, France
  3. 3Centre Hospitalier Universitaire, Clermont-Ferrand, France
  4. 4Progenika Biopharma, S.A., Derio, Spain
  5. 5Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands
  6. 6Dutch Initiative on Crohn and Colitis (ICC)
  7. 71st Department of Medicine, Semmelweis University, Budapest, Hungary
  8. 8Department of Gastroenterology, Spitalnetz Bern, Switzerland
  9. 9Peninsula Medical School, University of Exeter & Plymouth, Exeter, UK
  10. 10Department of Gastroenterology and Hepatology, University Medical Center Groningen and the University of Groningen, Groningen, The Netherlands
  11. 11Systems and Modeling Unit, Montefiore Institute, University of Liège, Liège, Belgium
  12. 12Bioinformatics and Modeling, GIGA-R, University of Liège, Liège, Belgium
  13. 13Clinical and Experimental Sciences, Faculty of medicine, University of Southampton, Southampton, UK
  14. 14Department of Morphology and Molecular Pathology, University Hospital Gasthuisberg, Leuven, Belgium
  15. 15Department of Clinical Research, University of Bern, Bern, Switzerland
  16. 16Hungarian National Blood Transfusion Service, Molecular Diagnostics, Budapest, Hungary
  17. 17Division of Digestive Diseases, Inflammatory Bowel Diseases Center, UCLA, Los Angeles, USA
  18. 18Department of Genetics, University Medical Center Groningen and the University of Groningen, Groningen, The Netherlands
  19. 19Department of Rheumatology, Clinical Immunology and Allergology, University Hospital of Bern, Inselspital, Switzerland
  1. Correspondence to Dr Isabelle Cleynen, Targid—Translational Research Center for Gastrointestinal Disorders, IBD Leuven, Herestraat 49, O&N1, Box 701, Leuven 3000, Belgium; isabelle.cleynen{at}med.kuleuven.be; http://www.ibdase.org and Dr Arlette Darfeuille-Michaud, M2iSH, Inserm 1071, CBRV, 28 Place Henri Dunant, Clermont-Ferrand 63000, France; arlette.darfeuille-michaud{at}udamail.fr

Abstract

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.

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.

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 (pFDR=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-κB regulator CYLD. This resulted in IκB-α degradation and NF-κB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly.

Conclusions Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors.

  • BACTERIAL PATHOGENESIS
  • IBD - GENETICS
  • IBD BASIC RESEARCH
  • INFLAMMATORY BOWEL DISEASE
  • MOLECULAR GENETICS

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