Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2020 May 17

PMID 32414011

Citations 7

Authors

Matthew D Strub

Paul B McCray Jr

Affiliations

Soon will be listed here.

Abstract

Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator () gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for therapeutic development. The observation that the Phe508del-CFTR mutant protein is temperature sensitive provided proof of principle that mutant CFTR could escape proteosomal degradation and retain partial function. Several specific protein interactors and quality control checkpoints encountered by CFTR during its proteostasis have been investigated for therapeutic purposes, but remain incompletely understood. Furthermore, pharmacological manipulation of many CFTR interactors has not been thoroughly investigated for the rescue of Phe508del-CFTR. However, high-throughput screening technologies helped identify several small molecule modulators that rescue CFTR from proteosomal degradation and restore partial function to the protein. Here, we discuss the current state of CFTR transcriptomic and biogenesis research and small molecule therapy development. We also review recent progress in CFTR proteostasis modulators and discuss how such treatments could complement current FDA-approved small molecules.

Citing Articles

A Proteomic Survey of the Cystic Fibrosis Transmembrane Conductance Regulator Surfaceome.

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References

Liu F, Zhang Z, Csanady L, Gadsby D, Chen J . Molecular Structure of the Human CFTR Ion Channel. Cell. 2017; 169(1):85-95.e8. DOI: 10.1016/j.cell.2017.02.024. View

Mogk A, Ruger-Herreros C, Bukau B . Cellular Functions and Mechanisms of Action of Small Heat Shock Proteins. Annu Rev Microbiol. 2019; 73:89-110. DOI: 10.1146/annurev-micro-020518-115515. View

Davies J, Wainwright C, Canny G, Chilvers M, Howenstine M, Munck A . Efficacy and safety of ivacaftor in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013; 187(11):1219-25. PMC: 3734608. DOI: 10.1164/rccm.201301-0153OC. View

Bouchecareilh M, Hutt D, Szajner P, Flotte T, Balch W . Histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA)-mediated correction of α1-antitrypsin deficiency. J Biol Chem. 2012; 287(45):38265-78. PMC: 3488095. DOI: 10.1074/jbc.M112.404707. View

Brown C, Welch W . Correcting temperature-sensitive protein folding defects. J Clin Invest. 1997; 99(6):1432-44. PMC: 507959. DOI: 10.1172/JCI119302. View

Clancy J, Rowe S, Bebok Z, Aitken M, Gibson R, Zeitlin P . No detectable improvements in cystic fibrosis transmembrane conductance regulator by nasal aminoglycosides in patients with cystic fibrosis with stop mutations. Am J Respir Cell Mol Biol. 2007; 37(1):57-66. PMC: 1899350. DOI: 10.1165/rcmb.2006-0173OC. View

Harada K, Okiyoneda T, Hashimoto Y, Ueno K, Nakamura K, Yamahira K . Calreticulin negatively regulates the cell surface expression of cystic fibrosis transmembrane conductance regulator. J Biol Chem. 2006; 281(18):12841-8. DOI: 10.1074/jbc.M512975200. View

Boyle M, De Boeck K . A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect. Lancet Respir Med. 2014; 1(2):158-63. DOI: 10.1016/S2213-2600(12)70057-7. View

Sokol R . Infertility in men with cystic fibrosis. Curr Opin Pulm Med. 2001; 7(6):421-6. DOI: 10.1097/00063198-200111000-00011. View

10.

Riordan J, Rommens J, Kerem B, Alon N, Rozmahel R, Grzelczak Z . Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989; 245(4922):1066-73. DOI: 10.1126/science.2475911. View

11.

Scott-Ward T, Amaral M . Deletion of Phe508 in the first nucleotide-binding domain of the cystic fibrosis transmembrane conductance regulator increases its affinity for the heat shock cognate 70 chaperone. FEBS J. 2009; 276(23):7097-109. DOI: 10.1111/j.1742-4658.2009.07421.x. View

12.

Denning G, Ostedgaard L, Welsh M . Abnormal localization of cystic fibrosis transmembrane conductance regulator in primary cultures of cystic fibrosis airway epithelia. J Cell Biol. 1992; 118(3):551-9. PMC: 2289545. DOI: 10.1083/jcb.118.3.551. View

13.

Zhang Z, Liu F, Chen J . Conformational Changes of CFTR upon Phosphorylation and ATP Binding. Cell. 2017; 170(3):483-491.e8. DOI: 10.1016/j.cell.2017.06.041. View

14.

Zhang H, Schmidt B, Sun F, Condliffe S, Butterworth M, Youker R . Cysteine string protein monitors late steps in cystic fibrosis transmembrane conductance regulator biogenesis. J Biol Chem. 2006; 281(16):11312-21. DOI: 10.1074/jbc.M512013200. View

15.

Zielenski J, Tsui L . Cystic fibrosis: genotypic and phenotypic variations. Annu Rev Genet. 1995; 29:777-807. DOI: 10.1146/annurev.ge.29.120195.004021. View

16.

Pesce E, Gorrieri G, Sirci F, Napolitano F, Carrella D, Caci E . Evaluation of a systems biology approach to identify pharmacological correctors of the mutant CFTR chloride channel. J Cyst Fibros. 2016; 15(4):425-35. DOI: 10.1016/j.jcf.2016.02.009. View

17.

Mehnert M, Sommer T, Jarosch E . Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane. Nat Cell Biol. 2013; 16(1):77-86. DOI: 10.1038/ncb2882. View

18.

Howard M, Frizzell R, Bedwell D . Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med. 1996; 2(4):467-9. DOI: 10.1038/nm0496-467. View

19.

Pedemonte N, Lukacs G, Du K, Caci E, Zegarra-Moran O, Galietta L . Small-molecule correctors of defective DeltaF508-CFTR cellular processing identified by high-throughput screening. J Clin Invest. 2005; 115(9):2564-71. PMC: 1190372. DOI: 10.1172/JCI24898. View

20.

Cheng J, Wang H, Guggino W . Modulation of mature cystic fibrosis transmembrane regulator protein by the PDZ domain protein CAL. J Biol Chem. 2003; 279(3):1892-8. DOI: 10.1074/jbc.M308640200. View