Work

Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators

Year: 2025

Type: article

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.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.

Source: iScience

DOI: 10.1016/j.isci.2025.111942

Authors: 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

Institutions: University of Lisbon, University of Regensburg, Centro de Química Estrutural, European Molecular Biology Laboratory, European Molecular Biology Laboratory

Language: English

Topic: Cystic Fibrosis Research Advances

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,240

Funders: Cystic Fibrosis Foundation, Gilead Sciences, Gilead Research Scholars, European Commission, Fundação para a Ciência e a Tecnologia, Sixth Framework Programme

Awards: G1483381719, G1570005492, G2107431112, Centro de Química Estrutural, Caracterização do controlo de qualidade do reticulo endoplasmatico para a proteína F508del-CFTR: potenciais alvos terapêuticos para a Fibrose Quística, G4127328906, G4479284926, G4640917888, Instituto de Biosistemas & Ciências Integrativas, Desvendando o mecanismo de ação de uma nova cinase reguladora do tráfego e atividade da proteína F508del-CFTR, Anoctamin 6 - A novel ion channel regulator with extended functions and significance in disease - - Anoctamins - identification of Novel Traffic Regulators and their Significance to Cystic Fibrosis, Instituto de Biosistemas & Ciências Integrativas, G671296436, G6997658380, G8191554803

OpenAlex ID: W4407058604

FWCI: 1.772

Cites: 78

Cited by: 3

Related to: 10