title: Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell lines.
abstract: BACKGROUND
  Many genetic diseases are due to defects in protein trafficking where the mutant protein is recognized by the quality control systems, retained in the endoplasmic reticulum (ER), and degraded by the proteasome. In many cases, the mutant protein retains function if it can be trafficked to its proper cellular location. We have identified structurally diverse correctors that restore the trafficking and function of the most common mutation causing cystic fibrosis, F508del-CFTR. Most of these correctors do not act directly as ligands of CFTR, but indirectly on other pathways to promote folding and correction. We hypothesize that these proteostasis regulators may also correct other protein trafficking diseases.
  
  
  METHODS
  To test our hypothesis, we used stable cell lines or transient transfection to express 2 well-studied trafficking disease mutations in each of 3 different proteins: the arginine-vasopressin receptor 2 (AVPR2, also known as V2R), the human ether-a-go-go-related gene (KCNH2, also known as hERG), and finally the sulfonylurea receptor 1 (ABCC8, also known as SUR1). We treated cells expressing these mutant proteins with 9 structurally diverse F508del-CFTR correctors that function through different cellular mechanisms and assessed whether correction occurred via immunoblotting and functional assays. Results were deemed significantly different from controls by a one-way ANOVA (p < 0.05).
  
  
  RESULTS
  Here we show that F508del-CFTR correctors RDR1, KM60 and KM57 also correct some mutant alleles of other protein trafficking diseases. We also show that one corrector, the cardiac glycoside ouabain, was found to alter the glycosylation of all mutant alleles tested.
  
  
  CONCLUSIONS
  Correctors of F508del-CFTR trafficking might have broader applications to other protein trafficking diseases.
authors: Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, McIntyre Medical Building, Montréal, Québec H3G 1Y6, Canada.
authors: Heidi M
authors: HM
authors: Sampson
authors: Hung
authors: H
authors: Lam
authors: Pei-Chun
authors: PC
authors: Chen
authors: Donglei
authors: D
authors: Zhang
authors: Cristina
authors: C
authors: Mottillo
authors: Myriam
authors: M
authors: Mirza
authors: Karim
authors: K
authors: Qasim
authors: Alvin
authors: A
authors: Shrier
authors: Show-Ling
authors: SL
authors: Shyng
authors: John W
authors: JW
authors: Hanrahan
authors: David Y
authors: DY
authors: Thomas
mesh_terms: D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000628:therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D050505:Mutant Proteins / Q000235:genetics; D018408:Patch-Clamp Techniques; D021381:Protein Transport; D012413:Rubidium / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D012413:Rubidium