title: Improved maturation of CFTR by an ER export signal.
abstract: 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-deltaF508, leads to the genetic disease cystic fibrosis. CFTR-deltaF508 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-deltaF508 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-deltaF508 from ER degradation indicates that the inability of CFTR-deltaF508 to leave the ER is unlikely to be due to a malfunctioning ER export signal.
authors: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland.
authors: Markus W
authors: MW
authors: Wendeler
authors: Oliver
authors: O
authors: Nufer
authors: Hans-Peter
authors: HP
authors: Hauri
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006801:Humans; D007668:Kidney; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: C505032:CFTR protein, human; D011994:Recombinant Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator