Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease

Isabelle Cleynen, Emilie Vazeille, Marta Artieda, Hein W. Verspaget, Magdalena Szczypiorska, Marie Agnès Bringer, P. Lakatos, Frank Seibold, Kirstie Parnell, Rinse K. Weersma, Jestinah M. Mahachie John, Rebecca Morgan-Walsh, Dominiek Staelens, Ingrid Arijs, Gert De Hertogh, Stefan Müller, A. Tordai, Daniel W. Hommes, Tariq Ahmad, Cisca WijmengaSylvia Pender, Paul Rutgeerts, Kristel Van Steen, Daniel Lottaz, Severine Vermeire, Arlette Darfeuille-Michaud

Research output: Contribution to journalArticle

33 Citations (Scopus)

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 adherentinvasive 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.

Original languageEnglish
Pages (from-to)1265-1274
Number of pages10
JournalGut
Volume63
Issue number8
DOIs
Publication statusPublished - 2014

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Microbial Genetics
Proteasome Endopeptidase Complex
Ubiquitin
Inflammatory Bowel Diseases
Crohn Disease
Escherichia coli
Single Nucleotide Polymorphism
Genes
Genetic Association Studies
Polyubiquitin
Microbiota
Protease Inhibitors
Causality
Proteolysis
Virulence
Homeostasis
Peptide Hydrolases
Referral and Consultation
Epithelial Cells
Infection

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Cleynen, I., Vazeille, E., Artieda, M., Verspaget, H. W., Szczypiorska, M., Bringer, M. A., ... Darfeuille-Michaud, A. (2014). Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease. Gut, 63(8), 1265-1274. https://doi.org/10.1136/gutjnl-2012-303205

Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease. / Cleynen, Isabelle; Vazeille, Emilie; Artieda, Marta; Verspaget, Hein W.; Szczypiorska, Magdalena; Bringer, Marie Agnès; Lakatos, P.; Seibold, Frank; Parnell, Kirstie; Weersma, Rinse K.; Mahachie John, Jestinah M.; Morgan-Walsh, Rebecca; Staelens, Dominiek; Arijs, Ingrid; De Hertogh, Gert; Müller, Stefan; Tordai, A.; Hommes, Daniel W.; Ahmad, Tariq; Wijmenga, Cisca; Pender, Sylvia; Rutgeerts, Paul; Van Steen, Kristel; Lottaz, Daniel; Vermeire, Severine; Darfeuille-Michaud, Arlette.

In: Gut, Vol. 63, No. 8, 2014, p. 1265-1274.

Research output: Contribution to journalArticle

Cleynen, I, Vazeille, E, Artieda, M, Verspaget, HW, Szczypiorska, M, Bringer, MA, Lakatos, P, Seibold, F, Parnell, K, Weersma, RK, Mahachie John, JM, Morgan-Walsh, R, Staelens, D, Arijs, I, De Hertogh, G, Müller, S, Tordai, A, Hommes, DW, Ahmad, T, Wijmenga, C, Pender, S, Rutgeerts, P, Van Steen, K, Lottaz, D, Vermeire, S & Darfeuille-Michaud, A 2014, 'Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease', Gut, vol. 63, no. 8, pp. 1265-1274. https://doi.org/10.1136/gutjnl-2012-303205
Cleynen I, Vazeille E, Artieda M, Verspaget HW, Szczypiorska M, Bringer MA et al. Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease. Gut. 2014;63(8):1265-1274. https://doi.org/10.1136/gutjnl-2012-303205
Cleynen, Isabelle ; Vazeille, Emilie ; Artieda, Marta ; Verspaget, Hein W. ; Szczypiorska, Magdalena ; Bringer, Marie Agnès ; Lakatos, P. ; Seibold, Frank ; Parnell, Kirstie ; Weersma, Rinse K. ; Mahachie John, Jestinah M. ; Morgan-Walsh, Rebecca ; Staelens, Dominiek ; Arijs, Ingrid ; De Hertogh, Gert ; Müller, Stefan ; Tordai, A. ; Hommes, Daniel W. ; Ahmad, Tariq ; Wijmenga, Cisca ; Pender, Sylvia ; Rutgeerts, Paul ; Van Steen, Kristel ; Lottaz, Daniel ; Vermeire, Severine ; Darfeuille-Michaud, Arlette. / Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease. In: Gut. 2014 ; Vol. 63, No. 8. pp. 1265-1274.
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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 adherentinvasive 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.",
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T1 - Genetic and microbial factors modulating the ubiquitin proteasome system in inflammatory bowel disease

AU - Cleynen, Isabelle

AU - Vazeille, Emilie

AU - Artieda, Marta

AU - Verspaget, Hein W.

AU - Szczypiorska, Magdalena

AU - Bringer, Marie Agnès

AU - Lakatos, P.

AU - Seibold, Frank

AU - Parnell, Kirstie

AU - Weersma, Rinse K.

AU - Mahachie John, Jestinah M.

AU - Morgan-Walsh, Rebecca

AU - Staelens, Dominiek

AU - Arijs, Ingrid

AU - De Hertogh, Gert

AU - Müller, Stefan

AU - Tordai, A.

AU - Hommes, Daniel W.

AU - Ahmad, Tariq

AU - Wijmenga, Cisca

AU - Pender, Sylvia

AU - Rutgeerts, Paul

AU - Van Steen, Kristel

AU - Lottaz, Daniel

AU - Vermeire, Severine

AU - Darfeuille-Michaud, Arlette

PY - 2014

Y1 - 2014

N2 - 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 adherentinvasive 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.

AB - 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 adherentinvasive 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.

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