title: Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast.
abstract: 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.
authors.affiliation: Institut für Biochemie, Universität Stuttgart, 70569 Stuttgart, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Gnann
authors.forename: John R
authors.initials: JR
authors.lastname: Riordan
authors.forename: Dieter H
authors.initials: DH
authors.lastname: Wolf
mesh_terms: D000251:Adenosine Triphosphatases; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015870:Gene Expression; D005800:Genes, Fungal; D005816:Genetic Complementation Test; D006801:Humans; D066298:In Vitro Techniques; D037102:Lectins / Q000235:genetics / Q000378:metabolism; D008361:Mannosidases / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013696:Temperature; D000074405:Valosin Containing Protein; D033921:Vesicular Transport Proteins
chemical_list: C505032:CFTR protein, human; D018797:Cell Cycle Proteins; C434526:Edem1 protein, mouse; D037102:Lectins; D008565:Membrane Proteins; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C444652:UFD1 protein, S cerevisiae; D033921:Vesicular Transport Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C434527:MNL1 protein, S cerevisiae; D008361:Mannosidases; D000251:Adenosine Triphosphatases; C000614177:CDC48 protein, S cerevisiae; D000074405:Valosin Containing Protein