title: Human heat shock protein 105/110 kDa (Hsp105/110) regulates biogenesis and quality control of misfolded cystic fibrosis transmembrane conductance regulator at multiple levels.
abstract: Heat shock protein 105/110-kDa (Hsp105/110), a member of the Hsp70 super family of molecular chaperones, serves as a nucleotide exchange factor for Hsc70, independently prevents the aggregation of misfolded proteins, and functionally relates to Hsp90. We investigated the roles of human Hsp105α, the constitutively expressed isoform, in the biogenesis and quality control of the cystic fibrosis transmembrane conductance regulator (CFTR). In the endoplasmic reticulum (ER), Hsp105 facilitates CFTR quality control at an early stage in its biosynthesis but promotes CFTR post-translational folding. Deletion of Phe-508 (ΔF508), the most prevalent mutation causing cystic fibrosis, interferes with de novo folding of CFTR, impairing its export from the ER and accelerating its clearance in the ER and post-Golgi compartments. We show that Hsp105 preferentially associates with and stabilizes ΔF508 CFTR at both levels. Introduction of the Hsp105 substrate binding domain potently increases the steady state level of ΔF508 CFTR by reducing its early-stage degradation. This in turn dramatically enhances ΔF508 CFTR cell surface functional expression in cystic fibrosis airway epithelial cells. Although other Hsc70 nucleotide exchange factors such as HspBP1 and BAG-2 inhibit CFTR post-translational degradation in the ER through cochaperone CHIP, Hsp105 has a primary role promoting CFTR quality control at an earlier stage. The Hsp105-mediated multilevel regulation of ΔF508 CFTR folding and quality control provides new opportunities to understand how chaperone machinery regulates the homeostasis and functional expression of misfolded proteins in the cell. Future studies in this direction will inform therapeutics development for cystic fibrosis and other protein misfolding diseases.
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Saxena
authors.forename: Yeshavanth K
authors.initials: YK
authors.lastname: Banasavadi-Siddegowda
authors.forename: Yifei
authors.initials: Y
authors.lastname: Fan
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Gargi
authors.initials: G
authors.lastname: Roy
authors.forename: David R
authors.initials: DR
authors.lastname: Giovannucci
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Frizzell
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000473:pathology; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D050957:HSP110 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D055550:Protein Stability; D021381:Protein Transport; D059748:Proteolysis; D020545:Respiratory Mucosa / Q000166:cytology / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C492980:BAG2 protein, human; C505032:CFTR protein, human; D050883:HSC70 Heat-Shock Proteins; D050957:HSP110 Heat-Shock Proteins; C494371:HSPA8 protein, human; C116331:HSPBP1 protein, human; C097205:HSPH1 protein, human; D018832:Molecular Chaperones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator