TY - JOUR
T1 - Correction of F508del-CFTR trafficking by the sponge alkaloid latonduine is modulated by interaction with PARP
AU - Carlile, Graeme W.
AU - Keyzers, Robert A.
AU - Teske, Katrina A.
AU - Robert, Renaud
AU - Williams, David E.
AU - Linington, Roger G.
AU - Gray, Christopher A.
AU - Centko, Ryan M.
AU - Yan, Luping
AU - Anjos, Suzana M.
AU - Sampson, Heidi M.
AU - Zhang, Donglei
AU - Liao, Jie
AU - Hanrahan, John W.
AU - Andersen, Raymond J.
AU - Thomas, David Y.
N1 - Funding Information:
This work was funded by Canadian Institutes of Health Research (CIHR-CPG- 95270), the Canada Foundation for Innovation, and Cystic Fibrosis Canada.
PY - 2012/10/26
Y1 - 2012/10/26
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chembiol.2012.08.014
DO - 10.1016/j.chembiol.2012.08.014
M3 - Article
C2 - 23102222
AN - SCOPUS:84868012854
SN - 1074-5521
VL - 19
SP - 1288
EP - 1299
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 10
ER -
