Global Functional Genomics Reveals GRK5 as a Therapeutic Target for Cystic Fibrosis

Cystic Fibrosis (CF) is a life-shortening disease affecting >90,000 individuals worldwide predominantly with respiratory symptoms. About 80% of individuals with CF have the F508del mutation 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 F508del-CFTR, maximal lung function improvement is ~14% and the drug-targeted genes remain unknown.

To identify global modulators of F508del traffic, we performed a high-content siRNA microscopy-based screen of >9,000 genes and monitored F508del-CFTR PM rescue in human airway cells. This primary screen identified 227 F508del-CFTR traffic regulators, of which 35 could be validated by additional siRNAs. Subsequent mechanistic studies established GRK5 as a robust regulator whose inhibition rescues F508del-CFTR PM traffic, thus emerging as a novel potential drug target for CF.