Received for publication October 27, 2005.
Revised January 18, 2006.
Accepted for publication January 18, 2006.

Rescue of F508-CFTR by curcumin: involvement of the keratin 18 network

Abstract

The most common mutation in the CFTR gene, F508, causes retention of F508-CFTR in the endoplasmic reticulum and leads to the absence of CFTR Cl- channels in the plasma membrane. F508-CFTR retains some Cl- channel activity so increased expression of F508-CFTR in the plasma membrane can restore Cl- secretion deficiency. Recently, curcumin was shown to rescue F508-CFTR localization and function. In our previous work, the keratin 18 network was implicated in F508-CFTR trafficking. Here, we hypothesized that curcumin could restore a functional F508-CFTR to the plasma membrane acting via the K18 network. First, we analyzed the effects of curcumin on the localization of F508-CFTR in different cell lines (HeLa cells stably transfected with WT-CFTR or F508-CFTR, CALU-3 cells or CF pancreatic epithelial cells CFPAC-1) and found it was significantly delocalized towards the plasma membrane in F508-CFTR-expressing cells. We also performed a functional assay for the CFTR chloride channel in CFPAC-1 cells treated or not with curcumin and detected an increase in a cAMP-dependent chloride efflux in treated F508-CFTR-expressing cells. Then, the K18 network was analyzed by immunocytochemistry and immunoblot exclusively in curcumin-treated or untreated CFPAC-1 cells because of their endogenic F508-CFTR expression. After curcumin treatment, we observed a remodeling of the K18 network and a significant increase in K18 Ser52 phosphorylation, a site directly implicated in the reorganization of intermediate filaments. With these results, we propose K18 as a new therapeutic target and curcumin and/or its analogs might be considered as potential therapeutic agents for cystic fibrosis.

Key words: CFTR, Cystic Fibrosis, chloride secretion, curcumin, keratin 18, traffic

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