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

## TL;DR

A peptide targeting PI3Kγ improves CFTR function in cystic fibrosis, enhancing the effectiveness of existing therapies.

## Contribution

A novel peptide targeting PI3Kγ's AKAP function enhances CFTR membrane localization and modulator efficacy.

## Key findings

- PI3Kγ MP increases F508del-CFTR membrane localization and chloride secretion.
- PI3Kγ MP activates PKD1 via AKAP-Lbc, which is essential for enhancing CFTR expression.
- PKD1 inhibition blocks the beneficial effects of PI3Kγ MP on CFTR membrane expression.

## Abstract

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-activated chloride channel, cause cystic fibrosis (CF), the most common life-threatening inherited disorder among White individuals. Current CFTR correctors and potentiators, such as elexacaftor-tezacaftor-ivacaftor (ETI), only partially restore the function of the most prevalent mutant, F508del-CFTR, resulting in residual disease in people with CF. Here, we demonstrate that a mimetic peptide targeting the A-kinase–anchoring protein (AKAP) function of PI3Kγ (PI3Kγ MP), and driving localized cAMP elevation, enhances F508del-CFTR membrane localization, maximizing ETI efficacy in restoring chloride secretion. Mechanistically, PI3Kγ MP activates an AKAP-Lbc–anchored pool of PKD1, a known regulator of membrane trafficking. Consistently, PKD1 inhibition prevents PI3Kγ MP from enhancing the membrane expression of ETI-corrected F508del-CFTR. Overall, our findings reveal a regulatory pathway controlling CFTR membrane abundance via the AKAP function of PI3Kγ, which can be targeted to overcome the limitations of current CFTR modulator therapies.

A peptide targeting PI3Kγ boosts airway CFTR membrane localization, offering a new strategy to enhance the efficacy cystic fibrosis therapies