Botelho, Hugo M. and Lopes-Pacheco, Miqueias and Pinto, Madalena C. and Railean, Violeta and Pankonien, Ines and Caleiro, Mariana F. and Clarke, Luka A. and Cachatra, Vasco and Neumann, Beate and Tischer, Christian and Moiteiro, Cristina and Ousingsawat, Jiraporn and Kunzelmann, Karl and Pepperkok, Rainer and Amaral, Margarida D. (2025) Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators. ISCIENCE, 28 (3): 111942. ISSN , 2589-0042
Full text not available from this repository. (Request a copy)Abstract
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.Phe508delCFTR 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TRANSMEMBRANE CONDUCTANCE REGULATOR; PROTEIN-COUPLED RECEPTOR; DELTA-F508 CFTR; TEZACAFTOR-IVACAFTOR; ADENYLATE-CYCLASE; LOW-TEMPERATURE; MUTANT CFTR; MEMBRANE; RESCUE; IDENTIFICATION; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 May 2026 05:33 |
| Last Modified: | 19 May 2026 05:33 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67486 |
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