CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway.
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.
['Ruan|Ye Chun|YC|', 'Wang|Yan|Y|', 'Da Silva|Nicolas|N|', 'Kim|Bongki|B|', 'Diao|Rui Ying|RY|', 'Hill|Eric|E|', 'Brown|Dennis|D|', 'Chan|Hsiao Chang|HC|', 'Breton|Sylvie|S|']
D000818:Animals D002454:Cell Differentiation D002467:Cell Nucleus D002478:Cells, Cultured D019938:Cyclin D1 D003550:Cystic Fibrosis D019005:Cystic Fibrosis Transmembrane Conductance Regulator D004268:DNA-Binding Proteins D004847:Epithelial Cells D005786:Gene Expression Regulation D006801:Humans D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D038081:Organogenesis D011485:Protein Binding D021381:Protein Transport D018719:Receptor, ErbB-2 D015398:Signal Transduction D019108:Tight Junctions D014157:Transcription Factors D062826:Zonula Occludens-1 Protein
CFTR ZO-1 ZONAB Embryonic development Epithelial remodeling Male fertility Morphogenesis Proliferation