Received for publication April 1, 2004.
Revised August 3, 2004.
Accepted for publication August 3, 2004.

Molecular dissection of butyrate action revealed the involvement of MAPK in CFTR biogenesis

Abstract

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which belongs to the superfamily of ABC transporters and uniquely possesses an additional large cytoplasmic domain (R domain). CFTR inefficiently folds by means of co- and post-translational interactions with the cytosolic chaperones as well as ER lumenal chaperones in the ER. Aberrant folding and defective trafficking of the CFTR protein, which functions as an apical membrane Cl- channel, is the principal cause of cystic fibrosis. Recent data indicated that butyrate improves CFTR trafficking, in part, by regulating molecular chaperones. However, the precise mechanism of butyrate action remains elusive. In the present study, we examine the molecular aspect underlying the butyrate action in CFTR biogenesis, by evaluating the expression and localization of the GFP-tagged CFTR transgenes in Cos7 cells. Our data show that butyrate significantly promoted stability of the ER-located form of GFP-wt- CFTR, followed by an increase in the amount of plasma membrane GFP-wt-CFTR. In contrast, the expression of the R domain deletion mutant, GFP-R-CFTR, was slightly increased by butyrate. The butyrate action on wt-CFTR expression was partially blocked by PD98059, a specific inhibitor of MAPKK/MEK which is the upstream activator of ERK/MAPK. Furthermore, activation of ERK/MAPK by coexpression of constitutively active MAPKK/MEK predominantly augmented the expression of wt- CFTR, but not of R-CFTR, induced by butyrate. These data suggest that butyrate may facilitate the biogenesis and trafficking of wt-CFTR by requiring the presence of the R domain, and further involving active ERK/MAPK in its biogenesis.

Key words: MAP Kinase, Ion transporters (SERCA, Na/K ATPase, CFTR), Regulation of gene expression, Regulation - post-transcriptional

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