title: Multiple proteolytic systems, including the proteasome, contribute to CFTR processing.
abstract: The molecular components of the quality control system that rapidly degrades abnormal membrane and secretory proteins have not been identified. The cystic fibrosis transmembrane conductance regulator (CFTR) is an integral membrane protein to which this quality control is stringently applied; approximately 75% of the wild-type precursor and 100% of the delta F508 CFTR variant found in most CF patients are rapidly degraded before exiting from the ER. We now show that this ER degradation is sensitive to inhibitors of the cytosolic proteasome, including lactacystin and certain peptide aldehydes. One of the latter compounds, MG-132, also completely blocks the ATP-dependent conversion of the wild-type precursor to the native folded form that enables escape from degradation. Hence, CFTR and presumably other intrinsic membrane proteins are substrates for proteasomal degradation during their maturation within the ER.
authors.affiliation: S. C. Johnson Medical Research Center, Mayo Clinic Scottsdale, Arizona 85259, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Jensen
authors.forename: M A
authors.initials: MA
authors.lastname: Loo
authors.forename: S
authors.initials: S
authors.lastname: Pind
authors.forename: D B
authors.initials: DB
authors.lastname: Williams
authors.forename: A L
authors.initials: AL
authors.lastname: Goldberg
authors.forename: J R
authors.initials: JR
authors.lastname: Riordan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C505032:CFTR protein, human; D007976:Leupeptins; D009097:Multienzyme Complexes; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D014452:Ubiquitins; C063261:acetylleucyl-leucyl-norleucinal; C069861:calpain inhibitor 2; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C067713:lactacystin; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine