Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast

Cystic fibrosis is the most widespread hereditary disease among the white population caused by different mutations of the apical membrane ATP-binding cassette transporter cystic fibrosis transmembrane conductance regulator (CFTR). Its most common mutation, DeltaF508, leads to nearly complete degrada...

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Bibliographic Details
Published in:Molecular biology of the cell 2004-09, Vol.15 (9), p.4125-4135
Main Authors: Gnann, Andreas, Riordan, John R, Wolf, Dieter H
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases
Animals
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Endoplasmic Reticulum - metabolism
Gene Expression
Genes, Fungal
Genetic Complementation Test
Humans
In Vitro Techniques
Lectins - genetics
Lectins - metabolism
Mannosidases - genetics
Mannosidases - metabolism
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mutation
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Saccharomyces cerevisiae
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - genetics
Saccharomyces cerevisiae Proteins - metabolism
Temperature
Valosin Containing Protein
Vesicular Transport Proteins
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Summary:Cystic fibrosis is the most widespread hereditary disease among the white population caused by different mutations of the apical membrane ATP-binding cassette transporter cystic fibrosis transmembrane conductance regulator (CFTR). Its most common mutation, DeltaF508, leads to nearly complete degradation via endoplasmic reticulum-associated degradation (ERAD). Elucidation of the quality control and degradation mechanisms might give rise to new therapeutic approaches to cure this disease. In the yeast Saccharomyces cerevisiae, a variety of components of the protein quality control and degradation system have been identified. Nearly all of these components share homology with mammalian counterparts. We therefore used yeast mutants defective in the ERAD system to identify new components that are involved in human CFTR quality control and degradation. We show the role of the lectin Htm1p in the degradation process of CFTR. Complementation of the HTM1 deficiency in yeast cells by the mammalian orthologue EDEM underlines the necessity of this lectin for CFTR degradation and highlights the similarity of quality control and ERAD in yeast and mammals. Furthermore, degradation of CFTR requires the ubiquitin protein ligases Der3p/Hrd1p and Doa10p as well as the cytosolic trimeric Cdc48p-Ufd1p-Npl4p complex. These proteins also were found to be necessary for ERAD of a mutated yeast "relative" of CFTR, Pdr5(*)p.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.e04-01-0024