CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway

YC Ruan, Y Wang, N Da Silva, B Kim… - Journal of cell …, 2014 - journals.biologists.com
YC Ruan, Y Wang, N Da Silva, B Kim, RY Diao, E Hill, D Brown, HC Chan, S Breton
Journal of cell science, 2014journals.biologists.com
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 …
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 cftrΔF508 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.
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