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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2013

Open Access 01-12-2013 | Research

Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell lines

Authors: Heidi M Sampson, Hung Lam, Pei-Chun Chen, Donglei Zhang, Cristina Mottillo, Myriam Mirza, Karim Qasim, Alvin Shrier, Show-Ling Shyng, John W Hanrahan, David Y Thomas

Published in: Orphanet Journal of Rare Diseases | Issue 1/2013

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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.
Appendix
Available only for authorised users
Literature
1.
Brown CR, Hong-Brown LQ, Biwersi J, Verkman AS, Welch WJ: Chemical chaperones correct the mutant phenotype of the delta F508 cystic fibrosis transmembrane conductance regulator protein. Cell Stress Chaperones. 1996, 1: 117-125. 10.1379/1466-1268(1996)001<0117:CCCTMP>2.3.CO;2.PubMedCentralPubMedCrossRef
2.
Denning GM, Anderson MP, Amara JF, Marshall J, Smith AE, Welsh MJ: Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature. 1992, 358: 761-764. 10.1038/358761a0.PubMedCrossRef
3.
Rubenstein RC, Egan ME, Zeitlin PL: In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR. J Clin Invest. 1997, 100: 2457-2465. 10.1172/JCI119788.PubMedCentralPubMedCrossRef
4.
Asano N, Ishii S, Kizu H, Ikeda K, Yasuda K, Kato A, Martin OR, Fan JQ: In vitro inhibition and intracellular enhancement of lysosomal alpha-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives. Eur J Biochem. 2000, 267: 4179-4186. 10.1046/j.1432-1327.2000.01457.x.PubMedCrossRef
5.
Carlile GW, Robert R, Zhang D, Teske KA, Luo Y, Hanrahan JW, Thomas DY: Correctors of protein trafficking defects identified by a novel high-throughput screening assay. Chembiochem. 2007, 8: 1012-1020. 10.1002/cbic.200700027.PubMedCrossRef
6.
Fan JQ, Ishii S, Asano N, Suzuki Y: Accelerated transport and maturation of lysosomal alpha-galactosidase A in Fabry lymphoblasts by an enzyme inhibitor. Nat Med. 1999, 5: 112-115. 10.1038/4801.PubMedCrossRef
7.
Maegawa GH, Tropak M, Buttner J, Stockley T, Kok F, Clarke JT, Mahuran DJ: Pyrimethamine as a potential pharmacological chaperone for late-onset forms of GM2 gangliosidosis. J Biol Chem. 2007, 282: 9150-9161. 10.1074/jbc.M609304200.PubMedCentralPubMedCrossRef
8.
Sawkar AR, Cheng WC, Beutler E, Wong CH, Balch WE, Kelly JW: Chemical chaperones increase the cellular activity of N370S beta -glucosidase: a therapeutic strategy for Gaucher disease. Proc Natl Acad Sci USA. 2002, 99: 15428-15433. 10.1073/pnas.192582899.PubMedCentralPubMedCrossRef
9.
Tropak MB, Reid SP, Guiral M, Withers SG, Mahuran D: Pharmacological enhancement of beta-hexosaminidase activity in fibroblasts from adult Tay-Sachs and Sandhoff Patients. J Biol Chem. 2004, 279: 13478-13487. 10.1074/jbc.M308523200.PubMedCentralPubMedCrossRef
10.
Van Goor F, Straley KS, Cao D, Gonzalez J, Hadida S, Hazlewood A, Joubran J, Knapp T, Makings LR, Miller M, et al: Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules. Am J Physiol Lung Cell Mol Physiol. 2006, 290: L1117-L1130. 10.1152/ajplung.00169.2005.PubMedCrossRef
11.
Pedemonte N, Lukacs GL, Du K, Caci E, Zegarra-Moran O, Galietta LJ, Verkman AS: Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. J Clin Invest. 2005, 115: 2564-2571. 10.1172/JCI24898.PubMedCentralPubMedCrossRef
12.
Sampson HM, Robert R, Liao J, Matthes E, Carlile GW, Hanrahan JW, Thomas DY: Identification of a NBD1-Binding Pharmacological Chaperone that Corrects the Trafficking Defect of F508del-CFTR. Chem Biol. 2011, 18: 231-242. 10.1016/j.chembiol.2010.11.016.PubMedCrossRef
13.
Loo TW, Bartlett MC, Clarke DM: Rescue of DeltaF508 and other misprocessed CFTR mutants by a novel quinazoline compound. Mol Pharm. 2005, 2: 407-413. 10.1021/mp0500521.PubMedCrossRef
14.
Anjos SA, Robert R, Waller DD, Zhang D, Balghi H, Sampson HM, Ciciriello F, Lesimple P, Carlile G, Goepp J, et al: Decreasing Poly(ADP-ribose) Polymerase activity restores DeltaF508 CFTR trafficking. Front Pharmacol. 2012, 3: 165-PubMedCentralPubMedCrossRef
15.
Carlile GW, Keyzers RA, Teske KA, Robert R, Williams DE, Linington RG, Gray CA, Anjos SM, Sampson HM, Zhang D, et al: Correction of F508del-CFTR trafficking by the sponge alkaloid latonduine is modulated by interaction with PARP. Chem Biol. 2012, 19: 1288-1299. 10.1016/j.chembiol.2012.08.014.PubMedCrossRef
16.
Hutt DM, Herman D, Rodrigues AP, Noel S, Pilewski JM, Matteson J, Hoch B, Kellner W, Kelly JW, Schmidt A, et al: Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis. Nat Chem Biol. 2010, 6: 25-33. 10.1038/nchembio.275.PubMedCentralPubMedCrossRef
17.
Robert R, Carlile GC, Liao J, Balghi H, Lesimple P, Liu N, Kus B, Rotin D, Wilke M, de Jonge HR, et al: Correction of the Delta phe508 cystic fibrosis transmembrane conductance regulator trafficking defect by the bioavailable compound glafenine. Mol Pharmacol. 2010, 77: 922-930. 10.1124/mol.109.062679.PubMedCrossRef
18.
Robert R, Carlile GW, Pavel C, Liu N, Anjos SM, Liao J, Luo Y, Zhang D, Thomas DY, Hanrahan JW: Structural analog of sildenafil identified as a novel corrector of the F508del-CFTR trafficking defect. Mol Pharmacol. 2008, 73: 478-489.PubMedCrossRef
19.
Zhang D, Ciciriello F, Anjos SM, Carissimo A, Liao J, Carlile GW, Balghi H, Robert R, Luini A, Hanrahan JW, Thomas DY: Ouabain mimics low temperature rescue of F508del-CFTR in cystic fibrosis epithelial cells. Front Pharmacol. 2012, 3: 176-PubMedCentralPubMed
20.
Penning TD, Zhu GD, Gandhi VB, Gong J, Liu X, Shi Y, Klinghofer V, Johnson EF, Donawho CK, Frost DJ, et al: Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J Med Chem. 2009, 52: 514-523. 10.1021/jm801171j.PubMedCrossRef
21.
Hidvegi T, Ewing M, Hale P, Dippold C, Beckett C, Kemp C, Maurice N, Mukherjee A, Goldbach C, Watkins S, et al: An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science. 2010, 329: 229-232. 10.1126/science.1190354.PubMedCrossRef
22.
Rogawski MA, Loscher W: The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med. 2004, 10: 685-692. 10.1038/nm1074.PubMedCrossRef
23.
Feng L, Kwok IS-W, Bhatt P, Kaczmatek S, Valdez R, Layer E, Fitzpatrick RJ, Kolodziej AF: RDR-1: Correction and interaction with DeltaF508-NBD1. Pediatr Pulmonol. 2012, 47: 224-225.
24.
Robben JH, Knoers NV, Deen PM: Characterization of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus in a polarized cell model. Am J Physiol Renal Physiol. 2005, 289: F265-F272. 10.1152/ajprenal.00404.2004.PubMedCrossRef
25.
Tan CM, Nickols HH, Limbird LE: Appropriate polarization following pharmacological rescue of V2 vasopressin receptors encoded by X-linked nephrogenic diabetes insipidus alleles involves a conformation of the receptor that also attains mature glycosylation. J Biol Chem. 2003, 278: 35678-35686. 10.1074/jbc.M301888200.PubMedCrossRef
26.
Ficker E, Obejero-Paz CA, Zhao S, Brown AM: The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. J Biol Chem. 2002, 277: 4989-4998. 10.1074/jbc.M107345200.PubMedCrossRef
27.
Furutani M, Trudeau MC, Hagiwara N, Seki A, Gong Q, Zhou Z, Imamura S, Nagashima H, Kasanuki H, Takao A, et al: Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. Circulation. 1999, 99: 2290-2294. 10.1161/01.CIR.99.17.2290.PubMedCrossRef
28.
Chan KW, Zhang H, Logothetis DE: N-terminal transmembrane domain of the SUR controls trafficking and gating of Kir6 channel subunits. EMBO J. 2003, 22: 3833-3843. 10.1093/emboj/cdg376.PubMedCentralPubMedCrossRef
29.
Yang K, Fang K, Fromondi L, Chan KW: Low temperature completely rescues the function of two misfolded K ATP channel disease-mutants. FEBS Lett. 2005, 579: 4113-4118. 10.1016/j.febslet.2005.06.039.PubMedCrossRef
30.
Wible BA, Hawryluk P, Ficker E, Kuryshev YA, Kirsch G, Brown AM: HERG-Lite: a novel comprehensive high-throughput screen for drug-induced hERG risk. J Pharmacol Toxicol Methods. 2005, 52: 136-145. 10.1016/j.vascn.2005.03.008.PubMedCrossRef
31.
Walker VE, Atanasiu R, Lam H, Shrier A: Co-chaperone FKBP38 promotes HERG trafficking. J Biol Chem. 2007, 282: 23509-23516. 10.1074/jbc.M701006200.PubMedCrossRef
32.
Yan F, Lin CW, Weisiger E, Cartier EA, Taschenberger G, Shyng SL: Sulfonylureas correct trafficking defects of ATP-sensitive potassium channels caused by mutations in the sulfonylurea receptor. J Biol Chem. 2004, 279: 11096-11105. 10.1074/jbc.M312810200.PubMedCrossRef
33.
Robben JH, Sze M, Knoers NV, Deen PM: Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus. Am J Physiol Renal Physiol. 2007, 292: F253-F260.PubMedCrossRef
34.
Wang L, Wible BA, Wan X, Ficker E: Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking. J Pharmacol Exp Ther. 2007, 320: 525-534.PubMedCrossRef
35.
Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC: A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA. 2000, 97: 12329-12333. 10.1073/pnas.210244497.PubMedCentralPubMedCrossRef
36.
Yan FF, Casey J, Shyng SL: Sulfonylureas correct trafficking defects of disease-causing ATP-sensitive potassium channels by binding to the channel complex. J Biol Chem. 2006, 281: 33403-33413. 10.1074/jbc.M605195200.PubMedCrossRef
37.
Robben JH, Kortenoeven ML, Sze M, Yae C, Milligan G, Oorschot VM, Klumperman J, Knoers NV, Deen PM: Intracellular activation of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus by nonpeptide agonists. Proc Natl Acad Sci USA. 2009, 106: 12195-12200. 10.1073/pnas.0900130106.PubMedCentralPubMedCrossRef
38.
Campbell JD, Proks P, Lippiat JD, Sansom MS, Ashcroft FM: Identification of a functionally important negatively charged residue within the second catalytic site of the SUR1 nucleotide-binding domains. Diabetes. 2004, 53 (Suppl 3): S123-S127.PubMedCrossRef
39.
Lingrel JB: The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na,K-ATPase. Annu Rev Physiol. 2010, 72: 395-412. 10.1146/annurev-physiol-021909-135725.PubMedCentralPubMedCrossRef
40.
Beheshti Zavareh R, Lau KS, Hurren R, Datti A, Ashline DJ, Gronda M, Cheung P, Simpson CD, Liu W, Wasylishen AR, et al: Inhibition of the sodium/potassium ATPase impairs N-glycan expression and function. Cancer Res. 2008, 68: 6688-6697. 10.1158/0008-5472.CAN-07-6833.PubMedCrossRef
Metadata
Title
Compounds that correct F508del-CFTR trafficking can also correct other protein trafficking diseases: an in vitro study using cell lines
Authors
Heidi M Sampson
Hung Lam
Pei-Chun Chen
Donglei Zhang
Cristina Mottillo
Myriam Mirza
Karim Qasim
Alvin Shrier
Show-Ling Shyng
John W Hanrahan
David Y Thomas
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2013
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/1750-1172-8-11

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