title: Defective CFTR- β-catenin interaction promotes NF-κB nuclear translocation and intestinal inflammation in cystic fibrosis.
abstract: While inflammation with aberrant activation of NF-κB pathway is a hallmark of cystic fibrosis (CF), the molecular mechanisms underlying the link between CFTR defect and activation of NF-κB-mediated pro-inflammatory response remain elusive. Here, we investigated the link between CFTR defect and NF-κB activation in ΔF508cftr-/- mouse intestine and human intestinal epithelial cell lines. Our results show that the NF-κB/COX-2/PGE2 pathway is activated whereas the β-catenin pathway is suppressed in CF mouse intestine and CFTR-knockdown cells. Activation of β-catenin pathway by GSK3 inhibitors suppresses CFTR mutation/knockdown-induced NF-κB/COX-2/PGE2 pathway in ΔF508 mouse intestine and CFTR-knockdown cells. In contrast, suppression of β-catenin signaling induces the nuclear translocation of NF-κB. In addition, CFTR co-localizes and interacts with β-catenin while CFTR mutation disrupts the interaction between NF-κB and β-catenin in mouse intestine. Treatment with proteasome inhibitor MG132 completely reverses the reduced expression of β-catenin in Caco-2 cells. Collectively, these results indicate that CFTR stabilizes β-catenin and prevents its degradation, defect of which results in the activation of NF-κB-mediated inflammatory cascade. The present study has demonstrated a previously unsuspected interaction between CFTR and β-catenin that regulates NF-κB nuclear translocation in mouse intestine. Therefore, our study provides novel insights into the physiological function of CFTR and pathogenesis of CF-related diseases in addition to the NF-κB-mediated intestinal inflammation seen in CF.
authors: Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors: Kaisheng
authors: K
authors: Liu
authors: Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.|Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, PR China.
authors: Xiaohu
authors: X
authors: Zhang
authors: Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors: Jie Ting
authors: JT
authors: Zhang
authors: Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.
authors: Lai Ling
authors: LL
authors: Tsang
authors: Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.|School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China.
authors: Xiaohua
authors: X
authors: Jiang
authors: Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China.|School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China.|Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, PR China.
authors: Hsiao Chang
authors: HC
authors: Chan
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D018938:Caco-2 Cells; D003550:Cystic Fibrosis / Q000235:genetics* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology*; D007976:Leupeptins / Q000737:chemistry; D051379:Mice; D018181:Mice, Inbred CFTR; D009154:Mutation; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D007976:Leupeptins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D051176:beta Catenin; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C073701:Nfkb1 protein, mouse; D038362:Glycogen Synthase Kinase 3; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: CFTR; NF-κB; inflammation; small intestine; β-catenin