Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators
Summary: Cystic fibrosis (CF) is a life-shortening disease affecting >160,000 individuals worldwide predominantly with respiratory symptoms. About 80% of individuals with CF have the p.Phe508del variant that causes the CF transmembrane conductance regulator (CFTR) protein to misfold and be target...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225002020 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849721113177751552 |
|---|---|
| author | Hugo M. Botelho Miquéias Lopes-Pacheco Madalena C. Pinto Violeta Railean Ines Pankonien Mariana F. Caleiro Luka A. Clarke Vasco Cachatra Beate Neumann Christian Tischer Cristina Moiteiro Jiraporn Ousingsawat Karl Kunzelmann Rainer Pepperkok Margarida D. Amaral |
| author_facet | Hugo M. Botelho Miquéias Lopes-Pacheco Madalena C. Pinto Violeta Railean Ines Pankonien Mariana F. Caleiro Luka A. Clarke Vasco Cachatra Beate Neumann Christian Tischer Cristina Moiteiro Jiraporn Ousingsawat Karl Kunzelmann Rainer Pepperkok Margarida D. Amaral |
| author_sort | Hugo M. Botelho |
| collection | DOAJ |
| description | Summary: Cystic fibrosis (CF) is a life-shortening disease affecting >160,000 individuals worldwide predominantly with respiratory symptoms. About 80% of individuals with CF have the p.Phe508del variant that causes the CF transmembrane conductance regulator (CFTR) protein to misfold and be targeted for premature degradation by the endoplasmic reticulum (ER) quality control (ERQC), thus preventing its plasma membrane (PM) traffic. Despite the recent approval of a “highly effective” drug rescuing p.Phe508del-CFTR, maximal lung function improvement is ∼14%. To identify global modulators of p.Phe508del traffic, we performed a high-content small interfering RNA (siRNA) microscopy-based screen of >9,000 genes and monitored p.Phe508del-CFTR PM rescue in human airway cells. This primary screen identified 227 p.Phe508del-CFTR traffic regulators, of which 35 could be validated by additional siRNAs. Subsequent mechanistic studies established GRK5 as a robust regulator whose inhibition rescues p.Phe508del-CFTR PM traffic and function in primary and immortalized cells, thus emerging as a novel potential drug target for CF. |
| format | Article |
| id | doaj-art-2bc0cff47acc422e867718e3b48d7880 |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-2bc0cff47acc422e867718e3b48d78802025-08-20T03:11:46ZengElsevieriScience2589-00422025-03-0128311194210.1016/j.isci.2025.111942Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulatorsHugo M. Botelho0Miquéias Lopes-Pacheco1Madalena C. Pinto2Violeta Railean3Ines Pankonien4Mariana F. Caleiro5Luka A. Clarke6Vasco Cachatra7Beate Neumann8Christian Tischer9Cristina Moiteiro10Jiraporn Ousingsawat11Karl Kunzelmann12Rainer Pepperkok13Margarida D. Amaral14BioISI – Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, PortugalBioISI – Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, PortugalBioISI – Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, Portugal; Department of Physiology, University of Regensburg, Universitätsstrasse 31, 93053 Regensburg, GermanyBioISI – Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, PortugalBioISI – Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, PortugalBioISI – Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, PortugalBioISI – Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, PortugalCentro de Química Estrutural, Institute of Molecular Sciences, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, PortugalCell Biology and Biophysics Unit and Advanced Light Microscopy Facility, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, GermanyCell Biology and Biophysics Unit and Advanced Light Microscopy Facility, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany; Centre for Bioimage Analysis, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, GermanyCentro de Química Estrutural, Institute of Molecular Sciences, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, PortugalDepartment of Physiology, University of Regensburg, Universitätsstrasse 31, 93053 Regensburg, GermanyDepartment of Physiology, University of Regensburg, Universitätsstrasse 31, 93053 Regensburg, GermanyCell Biology and Biophysics Unit and Advanced Light Microscopy Facility, European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, GermanyBioISI – Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, Portugal; Corresponding authorSummary: Cystic fibrosis (CF) is a life-shortening disease affecting >160,000 individuals worldwide predominantly with respiratory symptoms. About 80% of individuals with CF have the p.Phe508del variant that causes the CF transmembrane conductance regulator (CFTR) protein to misfold and be targeted for premature degradation by the endoplasmic reticulum (ER) quality control (ERQC), thus preventing its plasma membrane (PM) traffic. Despite the recent approval of a “highly effective” drug rescuing p.Phe508del-CFTR, maximal lung function improvement is ∼14%. To identify global modulators of p.Phe508del traffic, we performed a high-content small interfering RNA (siRNA) microscopy-based screen of >9,000 genes and monitored p.Phe508del-CFTR PM rescue in human airway cells. This primary screen identified 227 p.Phe508del-CFTR traffic regulators, of which 35 could be validated by additional siRNAs. Subsequent mechanistic studies established GRK5 as a robust regulator whose inhibition rescues p.Phe508del-CFTR PM traffic and function in primary and immortalized cells, thus emerging as a novel potential drug target for CF.http://www.sciencedirect.com/science/article/pii/S2589004225002020Cell biologyFunctional genomics |
| spellingShingle | Hugo M. Botelho Miquéias Lopes-Pacheco Madalena C. Pinto Violeta Railean Ines Pankonien Mariana F. Caleiro Luka A. Clarke Vasco Cachatra Beate Neumann Christian Tischer Cristina Moiteiro Jiraporn Ousingsawat Karl Kunzelmann Rainer Pepperkok Margarida D. Amaral Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators iScience Cell biology Functional genomics |
| title | Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators |
| title_full | Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators |
| title_fullStr | Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators |
| title_full_unstemmed | Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators |
| title_short | Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators |
| title_sort | global functional genomics reveals grk5 as a cystic fibrosis therapeutic target synergistic with current modulators |
| topic | Cell biology Functional genomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225002020 |
| work_keys_str_mv | AT hugombotelho globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT miqueiaslopespacheco globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT madalenacpinto globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT violetarailean globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT inespankonien globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT marianafcaleiro globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT lukaaclarke globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT vascocachatra globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT beateneumann globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT christiantischer globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT cristinamoiteiro globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT jirapornousingsawat globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT karlkunzelmann globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT rainerpepperkok globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators AT margaridadamaral globalfunctionalgenomicsrevealsgrk5asacysticfibrosistherapeutictargetsynergisticwithcurrentmodulators |