Correctors of mutant CFTR enhance subcortical cAMP/PKA signaling via ezrin phosphorylation and cytoskeleton organization

Author:

Abbattiscianni Anna C.1,Favia Maria1,Mancini Maria T.1,Cardone Rosa A.1,Guerra Lorenzo1,Monterisi Stefania2,Castellani Stefano3,Laselva Onofrio1,Di Sole Francesca4,Conese Massimo3,Zaccolo Manuela2,Casavola Valeria1

Affiliation:

1. Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Italy

2. Department of Physiology, Anatomy and Genetics, University of Oxford, UK

3. Department of Medical and Surgical Sciences, University of Foggia, Italy

4. Physiology and Pharmacology Department, Des Moines University, Des Moines, IA, USA

Abstract

The most common mutation of Cystic Fibrosis (CF) Transmembrane Regulator (CFTR) gene, F508del, produces a misfolded protein resulting in its defective trafficking to the cell surface and an impaired chloride secretion. Pharmacological treatments partially rescue F508del CFTR activity either directly by interacting with the mutant protein and/or indirectly by altering the cellular protein homeostasis. We show that the ezrin phosphorylation together with its binding to phosphatidylinositol-4,5-bisphosphate (PIP2) tethers the F508del CFTR to the actin cytoskeleton, stabilizing it on the apical membrane and rescues the sub-membrane compartmentalization of cAMP and activated PKA. Both trimethylangelicin (TMA) and VX-809 correctors, besides rescuing F508del CFTR dependent chloride secretion, restore the apical expression of phosphorylated ezrin and actin organization and increase cAMP and activated PKA sub-membrane compartmentalization in both primary and secondary CF airway cells. Latrunculin B treatment or expression of the inactive ezrin mutant T567A reverse TMA and VX-809-induced effects highlighting the role of corrector-dependent ezrin activation and actin re-organization in creating the conditions to generate a sub-cortical cAMP pool of adequate amplitude to activate the F508del CFTR-dependent chloride secretion.

Funder

Italian Cystic Fibrosis Foundation

British Heart Foundation

Publisher

The Company of Biologists

Subject

Cell Biology

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