title: Correction of F508del-CFTR trafficking by the sponge alkaloid latonduine is modulated by interaction with PARP.
abstract: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause CF. The most common mutation, F508 deletion, causes CFTR misfolding and endoplasmic reticulum retention, preventing it from trafficking to the cell surface. One approach to CF treatment is to identify compounds that correct the trafficking defect. We screened a marine extract collection and, after extract, deconvolution identified the latonduines as F508del-CFTR trafficking correctors that give functional correction in vivo. Using a biotinylated azido derivative of latonduine, we identified the poly(ADP-ribose) polymerase (PARP) family as latonduine target proteins. We show that latonduine binds to PARPs 1, 2, 3, 4, 5a, and 5b and inhibits PARP activity, especially PARP-3. Thus, latonduine corrects F508del-CFTR trafficking by modulating PARP activity. Latonduines represent pharmacologic agents for F508del-CFTR correction, and PARP-3 is a pathway for the development of CF treatments.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada. graeme.carlile@mcgill.ca
authors.forename: Graeme W
authors.initials: GW
authors.lastname: Carlile
authors.forename: Robert A
authors.initials: RA
authors.lastname: Keyzers
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Teske
authors.forename: Renaud
authors.initials: R
authors.lastname: Robert
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
authors.forename: Roger G
authors.initials: RG
authors.lastname: Linington
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Gray
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Centko
authors.forename: Luping
authors.initials: L
authors.lastname: Yan
authors.forename: Suzana M
authors.initials: SM
authors.lastname: Anjos
authors.forename: Heidi M
authors.initials: HM
authors.lastname: Sampson
authors.forename: Donglei
authors.initials: D
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Liao
authors.forename: John W
authors.initials: JW
authors.lastname: Hanrahan
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.forename: David Y
authors.initials: DY
authors.lastname: Thomas
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009154:Mutation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011161:Porifera / Q000737:chemistry; D011485:Protein Binding; D017510:Protein Folding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D000470:Alkaloids; D006575:Heterocyclic Compounds, 3-Ring; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; C093349:cystic fibrosis transmembrane conductance regulator delta F508; C478428:latonduine A; C478429:latonduine B; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D011065:Poly(ADP-ribose) Polymerases