title: CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway.
abstract: Mutations in CFTR lead to dysfunction of tubular organs, which is currently attributed to impairment of its conductive properties. We now show that CFTR regulates tight junction assembly and epithelial cell differentiation through modulation of the ZO-1-ZONAB pathway. CFTR colocalizes with ZO-1 at the tight junctions of trachea and epididymis, and is expressed before ZO-1 in Wolffian ducts. CFTR interacts with ZO-1 through the CTFR PDZ-binding domain. In a three-dimensional (3D) epithelial cell culture model, CFTR regulates tight junction assembly and is required for tubulogenesis. CFTR inhibition or knockdown reduces ZO-1 expression and induces the translocation of the transcription factor ZONAB (also known as YBX3) from tight junctions to the nucleus, followed by upregulation of the transcription of CCND1 and downregulation of ErbB2 transcription. The epididymal tubules of cftr(-/-) and cftr(ΔF508) mice have reduced ZO-1 levels, increased ZONAB nuclear expression, and decreased epithelial cell differentiation, illustrated by the reduced expression of apical AQP9 and V-ATPase. This study provides a new paradigm for the etiology of diseases associated with CFTR mutations, including cystic fibrosis.
authors.affiliation: Center for Systems Biology, Program in Membrane Biology, Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ye Chun
authors.initials: YC
authors.lastname: Ruan
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Systems Biology, Program in Membrane Biology, Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Da Silva
authors.affiliation: Center for Systems Biology, Program in Membrane Biology, Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Bongki
authors.initials: B
authors.lastname: Kim
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Rui Ying
authors.initials: RY
authors.lastname: Diao
authors.affiliation: Center for Systems Biology, Program in Membrane Biology, Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hill
authors.affiliation: Center for Systems Biology, Program in Membrane Biology, Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Brown
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
authors.affiliation: Center for Systems Biology, Program in Membrane Biology, Nephrology Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA Breton.sylvie@mgh.harvard.edu.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Breton
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038081:Organogenesis / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D019108:Tight Junctions / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D019938:Cyclin D1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004268:DNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D062826:Zonula Occludens-1 Protein; C505032:CFTR protein, human; C408323:Csda protein, mouse; C569042:TJP1 protein, human; C524056:Erbb2 protein, mouse
keywords: CFTR; Embryonic development; Epithelial remodeling; Male fertility; Morphogenesis; Proliferation; ZO-1; ZONAB
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