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Improved maturation of CFTR by an ER export signal

Biozentrum, University of Basel, Basel, Switzerland

³Correspondence: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland. E-mail: hans-peter.hauri{at}unibas.ch

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel in the plasma membrane of several epithelial cells. Maturation of CFTR is inefficient in most cells, with only a fraction of nascent chains being properly folded and transported to the cell surface. The most common mutation in CFTR, CFTR-F508, leads to the genetic disease cystic fibrosis. CFTR-F508 has a temperature-sensitive folding defect and is almost quantitatively degraded in the endoplasmic reticulum (ER). Here we tested whether a strong ER export signal appended to CFTR improves its transport and surface expression. We show that a single valine ER export signal at the C terminus of the cytoplasmic tail of CFTR improves maturation of wild-type CFTR by 2-fold. This conservative mutation interfered with neither plasma membrane localization nor stability of mature CFTR. In contrast, the valine signal was unable to rescue CFTR-F508 from ER-associated degradation. Our finding of improved maturation of CFTR mediated by a valine signal may be of potential use in gene therapy of cystic fibrosis. Moreover, failure of the valine signal to rescue CFTR-F508 from ER degradation indicates that the inability of CFTR-F508 to leave the ER is unlikely to be due to a malfunctioning ER export signal.—Wendeler, M. W., Nufer, O., Hauri, H-P. Improved maturation of CFTR by an ER export signal.

Key Words: cystic fibrosis • membrane traffic • transport signal