Cystic fibrosis (CF) is an inherited loss-of-function childhood disease in protein homeostasis (proteostasis). CF is caused principally by the Phe 508 deletion in the cystic fibrosis transmembrane conductance regulator (?F508 CFTR), a multi-membrane spanning, cAMP-regulated chloride channel. Misfolding and efficient degradation of ?F508 in the endoplasmic reticulum, the first step in the exocytic pathway, reduces the stability of the protein resulting in the loss of cell surface conductance, premature lung failure and shortened lifespan. CF is a member of a large group of misfolding diseases including childhood emphysema, lysosomal storage deficiencies, type II diabetes and neurodegenerative pathologies associated with aging that are defective in proteostasis. We now show that by modulating the epigenome with histone deacetylase (HDAC) inhibitors (HDACi), we can reprogram the lung cell environment to achieve a productive balance between the rate of ?F508 synthesis, folding, degradation and trafficking leading to conductance (function) at the cell surface. This corrective event occurs upon treatment of primary human bronchial epithelial (HBE) cells obtained from ?F homozygous patients (HBE-CF-(?F/?F) with the clinically approved HDACi SAHA to a level of functional cell surface channel activity that is considered corrective for disease. Specific knockdown by small interfering (si)-RNA of HDAC7 results in recovery of conductance in lung cells, suggesting that only a subset of HDAC activities modulates CFTR folding, stability, trafficking and function. We suggest that HVACs control a transcriptional program that is linked to proteostasis to achieve folding, stability, trafficking and function of ?F508 that can be protective for CF. In this proposal, we propose to develop specific small molecules to inhibit HDAC7 function (Aim 1) and to explore the role of HDAC7 in CF biology (Aim 2). Use of HDACi to chemically modulate linked transcriptional and protein homeostasis environments is anticipated to have high impact on correction of human misfolding disease.
Cystic fibrosis (CF) is an inherited loss-of-function childhood disease caused by mutation of the cystic fibrosis transmembrane conductance regulator (?F508 CFTR), a critical chloride channel in the lung. Misfolding and degradation of the mutant channel results in the loss of cell surface conductance, premature lung failure and shortened lifespan. We show that by modulating the cellular epigenome (events that control gene expression in the nucleus through modification of DNA organization), we can reprogram the lung cell environment to correct disease, demonstrating that pharmacological modulation of the protein composition of the cell through a novel group of drugs can have a high impact on correction of human misfolding disease.
|Hutt, Darren M; Loguercio, Salvatore; Roth, Daniela Martino et al. (2018) Correcting the F508del-CFTR variant by modulating eukaryotic translation initiation factor 3-mediated translation initiation. J Biol Chem 293:13477-13495|
|Wang, Chao; Balch, William E (2018) Bridging Genomics to Phenomics at Atomic Resolution through Variation Spatial Profiling. Cell Rep 24:2013-2028.e6|
|Hutt, Darren M; Mishra, Sanjay Kumar; Roth, Daniela Martino et al. (2018) Silencing of the Hsp70-specific nucleotide-exchange factor BAG3 corrects the F508del-CFTR variant by restoring autophagy. J Biol Chem 293:13682-13695|
|Hutt, Darren M; Loguercio, Salvatore; Campos, Alexandre Rosa et al. (2018) A Proteomic Variant Approach (ProVarA) for Personalized Medicine of Inherited and Somatic Disease. J Mol Biol 430:2951-2973|
|Pipalia, Nina H; Subramanian, Kanagaraj; Mao, Shu et al. (2017) Histone deacetylase inhibitors correct the cholesterol storage defect in most Niemann-Pick C1 mutant cells. J Lipid Res 58:695-708|
|Wang, Chao; Bouchecareilh, Marion; Balch, William E (2017) Measuring the Effect of Histone Deacetylase Inhibitors (HDACi) on the Secretion and Activity of Alpha-1 Antitrypsin. Methods Mol Biol 1639:185-193|
|Veit, Gudio; Avramescu, Radu G; Chiang, Annette N et al. (2016) From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol Biol Cell 27:424-33|
|Amaral, Margarida D; Balch, William E (2015) Hallmarks of therapeutic management of the cystic fibrosis functional landscape. J Cyst Fibros 14:687-99|
|Rauniyar, Navin; Subramanian, Kanagaraj; Lavallée-Adam, Mathieu et al. (2015) Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann-Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis. Mol Cell Proteomics 14:1734-49|
|Pankow, Sandra; Bamberger, Casimir; Calzolari, Diego et al. (2015) ?F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 528:510-6|
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