Targeting PI3Kγ anchoring enhances CFTR membrane localization and modulator efficacy via PKD1.

Area of Science:

• Molecular Biology
• Cell Biology
• Medical Genetics

Background:

• Cystic fibrosis (CF) is caused by mutations in the CFTR gene.
• Current CFTR modulators like ETI offer partial restoration of F508del-CFTR function, leaving residual disease.
• There is a need for therapies that maximize CFTR function and overcome current treatment limitations.

Purpose of the Study:

• To investigate a novel peptide targeting PI3Kγ's A-kinase-anchoring protein (AKAP) function to enhance F508del-CFTR function.
• To explore the mechanism by which PI3Kγ modulates CFTR membrane localization and activity.
• To determine if this approach can improve the efficacy of existing CFTR modulator therapies.

Main Methods:

• Utilized a mimetic peptide targeting the AKAP function of PI3Kγ (PI3Kγ MP).
• Assessed the effect of PI3Kγ MP on F508del-CFTR membrane localization and chloride secretion, alone and in combination with ETI.
• Investigated the role of protein kinase D1 (PKD1) in the PI3Kγ MP-mediated enhancement of CFTR function.

Main Results:

• PI3Kγ MP significantly enhanced F508del-CFTR membrane localization and chloride secretion.
• Combined treatment with PI3Kγ MP and ETI maximized ETI efficacy in restoring chloride transport.
• Activation of PKD1 was essential for PI3Kγ MP to enhance membrane expression of ETI-corrected F508del-CFTR.

Conclusions:

• A regulatory pathway involving the AKAP function of PI3Kγ controls CFTR membrane abundance.
• Targeting this pathway with PI3Kγ MP can overcome limitations of current CFTR modulator therapies.
• This approach represents a promising strategy to improve therapeutic outcomes for individuals with cystic fibrosis.