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

Yechun Ruan, Yan Wang, Nicolas da Silva, Bongki Kim, Rui Ying Diao, Eric Hill, Dennis Brown, Hsiao Chang Chan, Sylvie Breton

Research output: Journal article publicationJournal articleAcademic researchpeer-review

68 Citations (Scopus)

Abstract

Published by The Company of Biologists Ltd. 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 cftrΔF508mice 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.
Original languageEnglish
Pages (from-to)4396-4408
Number of pages13
JournalJournal of Cell Science
Volume127
Issue number20
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

Keywords

  • CFTR
  • Embryonic development
  • Epithelial remodeling
  • Male fertility
  • Morphogenesis
  • Proliferation
  • ZO-1
  • ZONAB

ASJC Scopus subject areas

  • Cell Biology

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