title: FK506 binding protein 8 peptidylprolyl isomerase activity manages a late stage of cystic fibrosis transmembrane conductance regulator (CFTR) folding and stability.
abstract: Cystic fibrosis (CF) is caused by mutations in the apical chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) with 90% of patients carrying at least one deletion of the F508 (ΔF508) allele. This mutant form of CFTR is characterized by a folding and trafficking defect that prevents exit from the endoplasmic reticulum. We previously reported that ΔF508 CFTR can be recovered in a complex with Hsp90 and its co-chaperones as an on-pathway folding intermediate, suggesting that Δ508 CF disease arises due to a failure of the proteostasis network (PN), which manages protein folding and degradation in the cell. We have now examined the role of FK506-binding protein 8 (FKBP8), a component of the CFTR interactome, during the biogenesis of wild-type and ΔF508 CFTR. FKBP8 is a member of the peptidylprolyl isomerase family that mediates the cis/trans interconversion of peptidyl prolyl bonds. Our results suggest that FKBP8 is a key PN factor required at a post-Hsp90 step in CFTR biogenesis. In addition, changes in its expression level or alteration of its activity by a peptidylprolyl isomerase inhibitor alter CFTR stability and transport. We propose that CF is caused by the sequential failure of the prevailing PN pathway to stabilize ΔF508-CFTR for endoplasmic reticulum export, a pathway that can be therapeutically managed.
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Hutt
authors.forename: Daniela Martino
authors.initials: DM
authors.lastname: Roth
authors.forename: Monica A
authors.initials: MA
authors.lastname: Chalfant
authors.forename: Robert T
authors.initials: RT
authors.lastname: Youker
authors.forename: Jeanne
authors.initials: J
authors.lastname: Matteson
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Brodsky
authors.forename: William E
authors.initials: WE
authors.lastname: Balch
mesh_terms: D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics*; D004247:DNA / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020104:Immunophilins / Q000378:metabolism; D007454:Iodides / Q000737:chemistry; D011489:Protein Denaturation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D022021:Tacrolimus Binding Proteins / Q000737:chemistry*; D013696:Temperature; D013997:Time Factors
chemical_list: C505032:CFTR protein, human; C471205:FKBP8 protein, human; D006360:Heat-Shock Proteins; D007454:Iodides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004247:DNA; D022021:Tacrolimus Binding Proteins; D020104:Immunophilins