CFTR Rescue by Lumacaftor (VX-809) Induces an Extensive Reorganization of Mitochondria in the Cystic Fibrosis Bronchial Epithelium
Abstract
:1. Introduction
1.1. CFTR Biogenesis
1.2. Protein Alterations in CF
2. Results
2.1. Relative Protein Expression Data
2.2. LOPIT-DC for F508del-CFTR CFBE41o- Cells
2.3. The CFBE41o- Subcellular Proteome before and after VX-809 Treatment
2.4. Identification of Differential Localized Proteins
2.5. CFTR Expression and Localization
2.6. Mitochondrial and Peroxisomal Reorganization
3. Discussion
4. Materials and Methods
4.1. Chemicals, Reagents and Instruments
4.2. CFBE41o- Cell Culture
4.3. Expression Proteomics: Sample Preparation and SWATH Data Acquisition
4.4. SWATH Data Analysis
4.5. LOPIT-DC
Cell Culture and VX-809 Treatment
4.6. Cell Lysis and Subcellular Fractionation
4.7. Evaluation of Organelles Separation through Western-Blot (WB)
4.8. Protein Digestion and TMT Labelling
4.9. Peptide Fractionation and LC-MS/MS Analysis
4.10. LOPIT-DC Data Processing
4.11. Statistical Analysis of Differential Localization
4.12. Enrichment Analysis
4.13. YFP-Based Assay for CFTR Activity
4.14. CFTR Localization
4.15. Western Blot for the Evaluation of VX-809 Corrector Activity
4.16. Culture and Differentiation of Primary Bronchial Epithelial Cells
4.17. Analysis of CFTR-Mediated Transepithelial Ion Transport in Primary Bronchial Epithelial Cells
4.18. Analysis of Mitochondria Network and Peroxisomal Distribution
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Accession | Protein Name | Gene |
---|---|---|
Q8WVM0 | Dimethyladenosine transferase 1, mitochondrial | TFB1M |
Q9Y3B7 | 39S ribosomal protein L11 | MRPL11 |
U3KQ69 | Mitochondrial GTPase 1 | MTG1 |
Q969S9 | Ribosome-releasing factor 2 | GFM2 |
Q96E29 | Transcription termination factor 3 | MTERF3 |
O75616 | GTPase Era | ERAL1 |
Q4G0N4 | NAD kinase 2 | NADK2 |
Q5T440 | Putative transferase CAF17 | IBA57 |
Q96D53 | Atypical kinase COQ8B | COQ8B |
Q96DV4 | 39S ribosomal protein L38 | MRPL38 |
Q8TAE8 | Growth arrest and DNA damage-inducible protein | GADD45GIP1 |
Q96HY7 | 2-oxoglutarate dehydrogenase E1 | DHTKD1 |
P82933 | 28S ribosomal protein S9, mitochondrial | MRPS9 |
Organelle | Antigen | Supplier (Product Number) | Gene Name | MW (kDa) | Source | Dilution for WB |
---|---|---|---|---|---|---|
Cytosol | Alpha-Enolase | Cell signalling (3010) | ENO1 | 47 | Rabbit | 1:1000 |
Golgi | Syntaxin-6 | Abcam (ab140607) | STX6 | 32 | Rabbit | 1:1000 |
Plasma membrane | Alph-a1 Na+/K+ ATPase | Abcam (ab76020) | ATP1A1 | 100 | Rabbit | 1:5000 |
ER | Calreticulin | Abcam (ab92341) | CARL | 55 | Rabbit | 1:1000 |
Chromatin | Histone H2A | Abcam (ab18975) | HIST1H2AG | 14 | Rabbit | 1:1000 |
Endosome | Early endosome antigen 1 | Abcam (ab109110) | EEA1 | 170 | Rabbit | 1:1000 |
Lysosome | Lysosome-associated membrane glycoprotein 1 | Cell signalling (3243) | LAMP1 | 100 | Rabbit | 1:1000 |
Nuclear–non-chromatin | Fibrillarin | Cell signalling (2639) | FBL | 37 | Rabbit | 1:1000 |
Nuclear envelope | Prelamin-A/C | Abcam (ab108922) | LMNA | 70 | Rabbit | 1:1000 |
Mitochondria | Cytochrome c oxidase subunit 4 isoform 1 (COX 1V) | Cell signalling (4850) | COX4I1 | 17 | Rabbit | 1:1000 |
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Braccia, C.; Christopher, J.A.; Crook, O.M.; Breckels, L.M.; Queiroz, R.M.L.; Liessi, N.; Tomati, V.; Capurro, V.; Bandiera, T.; Baldassari, S.; et al. CFTR Rescue by Lumacaftor (VX-809) Induces an Extensive Reorganization of Mitochondria in the Cystic Fibrosis Bronchial Epithelium. Cells 2022, 11, 1938. https://doi.org/10.3390/cells11121938
Braccia C, Christopher JA, Crook OM, Breckels LM, Queiroz RML, Liessi N, Tomati V, Capurro V, Bandiera T, Baldassari S, et al. CFTR Rescue by Lumacaftor (VX-809) Induces an Extensive Reorganization of Mitochondria in the Cystic Fibrosis Bronchial Epithelium. Cells. 2022; 11(12):1938. https://doi.org/10.3390/cells11121938
Chicago/Turabian StyleBraccia, Clarissa, Josie A. Christopher, Oliver M. Crook, Lisa M. Breckels, Rayner M. L. Queiroz, Nara Liessi, Valeria Tomati, Valeria Capurro, Tiziano Bandiera, Simona Baldassari, and et al. 2022. "CFTR Rescue by Lumacaftor (VX-809) Induces an Extensive Reorganization of Mitochondria in the Cystic Fibrosis Bronchial Epithelium" Cells 11, no. 12: 1938. https://doi.org/10.3390/cells11121938
APA StyleBraccia, C., Christopher, J. A., Crook, O. M., Breckels, L. M., Queiroz, R. M. L., Liessi, N., Tomati, V., Capurro, V., Bandiera, T., Baldassari, S., Pedemonte, N., Lilley, K. S., & Armirotti, A. (2022). CFTR Rescue by Lumacaftor (VX-809) Induces an Extensive Reorganization of Mitochondria in the Cystic Fibrosis Bronchial Epithelium. Cells, 11(12), 1938. https://doi.org/10.3390/cells11121938