Molecular Chaperones as Targets to Circumvent the CFTR Defect in Cystic Fibrosis

Chanoux, Rebecca A.; Rubenstein, Ronald C.

doi:10.3389/fphar.2012.00137

Cited by 27 publications

(22 citation statements)

References 116 publications

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“…The binding cycle of Hsp90 seems to follow a similar story. Hsp90 is known to bind to proteins and promote folding (reviewed in 10; 100; 101; 102 ). Disruption of Hsp90 interactions with CFTR with the geldanamycin and herbimycin A decreased the maturation and increased degradation of CFTR in Chinese Hamster Ovary and Baby Hamster Kidney cells 75 .…”

Section: Discussionmentioning

confidence: 99%

“…This mutation is the most common and 90% of all patients with CF are either heterozygous or homozygous for this mutation. While there are reports that this synonymous codon replacement contributes to the disease state 8; 9 , most studies on the effect of F508del have concentrated on the folding and expression of CFTR due to the deletion of F508 (for review, see 10 ).…”

Section: Introductionmentioning

confidence: 99%

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Synonymous Codon Usage Affects the Expression of Wild Type and F508del CFTR

Shah

Cheng

Hahn

et al. 2015

Journal of Molecular Biology

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The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel composed of 1480 amino acids. The major mutation responsible for cystic fibrosis results in loss of amino acid residue, F508, (F508del). Loss of F508 in CFTR alters the folding pathway resulting in endoplasmic reticulum associated degradation (ERAD). This study investigates the role of synonymous codon in the expression of CFTR and CFTR F508del in human HEK293 cells. DNA encoding the open reading frame (ORF) for CFTR containing synonymous codon replacements, were expressed using a heterologous vector integrated into the genome. The results indicate that the codon usage greatly affects the expression of CFTR. While the promoter strength driving expression of the ORFs was largely unchanged and the mRNA half-lives were unchanged, the steady state levels of the mRNA varied by as much as 30 fold. Experiments support that this apparent inconsistency is attributed to exon junction complex independent nonsense mediated decay. The ratio of CFTR/mRNA indicates that mRNA containing native codons was more efficient in expressing mature CFTR as compared to mRNA containing synonymous high expression codons. However, when F508del CFTR was expressed after codon optimization, a greater percentage of the protein escaped ERAD resulting in considerable levels of mature F508del CFTR on the plasma membrane, which showed channel activity. These results indicate that for CFTR, codon usage has an effect on mRNA levels, protein expression and likely, for F508del CFTR, chaperone assisted folding pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synonymous Codon Usage Affects the Expression of Wild Type and F508del CFTR

Shah

Cheng

Hahn

et al. 2015

Journal of Molecular Biology

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“…Pharmacological chaperoning has emerged as a potential strategy to treat diseases cystic fibrosis [1–3], Gaucher’s disease [4,5], nephrogenic diabetes insipidus [6], retinitis pigmentosa [7,8] and some cancers resulting from mutations in p53 [9]. Notably, the treatment of transthyretin familial amyloid polyneuropathy with the pharmacological chaperone, tafamadis has been successful in a phase II/III clinical trial [10–13].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological chaperoning of nAChRs: A therapeutic target for Parkinson's disease

Srinivasan

Henderson

Lester

et al. 2014

Pharmacological Research

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Chronic exposure to nicotine results in an upregulation of neuronal nicotinic acetylcholine receptors (nAChRs) at the cellular plasma membrane. nAChR upregulation occurs via nicotine-mediated pharmacological receptor chaperoning and is thought to contribute to the addictive properties of tobacco as well as relapse following smoking cessation. At the subcellular level, pharmacological chaperoning by nicotine and nicotinic ligands causes profound changes in the structure and function of the endoplasmic reticulum (ER), ER exit sites, the Golgi apparatus and secretory vesicles of cells. Chaperoning-induced changes in cell physiology exert an overall inhibitory effect on the ER stress/unfolded protein response. Cell autonomous factors such as the repertoire of nAChR subtypes expressed by neurons and the pharmacological properties of nicotinic ligands (full or partial agonist versus competitive antagonist) govern the efficiency of receptor chaperoning and upregulation. Together, these findings are beginning to pave the way for developing pharmacological chaperones to treat Parkinson’s disease and nicotine addiction.

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“…This property combined with appropriate mutations can give rise to folding diseases, where a potentially functional protein is retained. The most prominent example is CFTRΔF508; a cytoplasmic chaperone relay system assists in quality control of CFTRΔF508 (45), and pharmacological manipulations of the relay system can in principle be employed to allow for escape of the protein to the cell surface (46). ABC transporters have large intracellular domains.…”

Section: Discussionmentioning

confidence: 99%

Recruitment of a Cytoplasmic Chaperone Relay by the A2A Adenosine Receptor

Bergmayr¹,

Thurner

Keuerleber

et al. 2013

Journal of Biological Chemistry

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Background: The A2A receptor is known to accumulate in the endoplasmic reticulum.Results: Mass spectrometry identified molecular chaperones (HSP90 and HSP70) bound to the A2A receptor.Conclusion: Sequential recruitment of chaperones to the cytosolic face of the A2A receptor is consistent with a heat-shock protein relay assisting folding.Significance: The observations are consistent with a chaperone/COPII exchange model, where heat-shock proteins bound to the receptor preclude its premature ER export.

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Molecular Chaperones as Targets to Circumvent the CFTR Defect in Cystic Fibrosis

Cited by 27 publications

References 116 publications

Synonymous Codon Usage Affects the Expression of Wild Type and F508del CFTR

Synonymous Codon Usage Affects the Expression of Wild Type and F508del CFTR

Pharmacological chaperoning of nAChRs: A therapeutic target for Parkinson's disease

Recruitment of a Cytoplasmic Chaperone Relay by the A2A Adenosine Receptor

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