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

Hugo M Botelho1, Miquéias Lopes-Pacheco1, Madalena C Pinto1,2

  • 1BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.

Iscience
|March 5, 2025
PubMed

Insights

Researchers screened over 9,000 genes to find ways to improve cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein traffic. Inhibiting GRK5 shows promise for rescuing CFTR function and offers a new drug target for CF treatment.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Cystic Fibrosis (CF) affects over 160,000 people globally, primarily causing respiratory issues.
  • The common p.Phe508del variant leads to misfolded CF transmembrane conductance regulator (CFTR) protein, preventing its transport to the cell surface.
  • Current treatments offer limited lung function improvement (∼14%) for p.Phe508del-CFTR variants.

Purpose of the Study:

  • To identify global regulators of p.Phe508del-CFTR protein traffic.
  • To discover novel therapeutic targets for enhancing CFTR protein delivery to the plasma membrane.

Main Methods:

  • Conducted a high-content, small interfering RNA (siRNA) microscopy-based screen of over 9,000 genes.
  • Monitored p.Phe508del-CFTR plasma membrane (PM) rescue in human airway cells.
  • Validated identified regulators through secondary siRNA screens and mechanistic studies.

Main Results:

  • Identified 227 potential regulators of p.Phe508del-CFTR traffic in the primary screen.
  • Validated 35 regulators with additional siRNAs.
  • Established GRK5 as a robust regulator; its inhibition rescues p.Phe508del-CFTR PM traffic and function.

Conclusions:

  • GRK5 inhibition represents a novel therapeutic strategy for cystic fibrosis.
  • Targeting GRK5 can improve p.Phe508del-CFTR trafficking and function in CF cells.
  • This study identifies potential new drug targets for CF treatment.
Keywords:
Cell biologyFunctional genomics

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