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Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
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Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein

Published on: March 9, 2015

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Roscovitine is a proteostasis regulator that corrects the trafficking defect of F508del-CFTR by a CDK-independent

C Norez1, C Vandebrouck, J Bertrand

  • 1Institut de Physiologie et Biologie Cellulaires, Université de Poitiers, Poitiers, France.

British Journal of Pharmacology
|July 29, 2014
PubMed
Abstract

Insights

Roscovitine corrects defective CFTR protein function in cystic fibrosis by improving its trafficking and channel activity. This compound offers potential as a novel pharmacological therapy for CF patients.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Pharmacology

Background:

  • Cystic Fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein, most commonly F508del.
  • The F508del mutation leads to protein misfolding, impaired trafficking, and defective channel function.
  • Current therapeutic strategies for CF are limited, necessitating novel approaches targeting the root cause.

Purpose of the Study:

  • To investigate roscovitine as a potential therapeutic agent for CF.
  • To elucidate the mechanism by which roscovitine corrects F508del-CFTR dysfunction.
  • To determine if roscovitine's effects are dependent on cyclin-dependent kinase (CDK) inhibition.

Main Methods:

  • Human CF airway epithelial cells were treated with roscovitine.
  • CFTR maturation, expression, and activity were assessed.
  • Mechanisms were explored by examining endoplasmic reticulum (ER) Ca(2+) levels, F508del-CFTR/calnexin interaction, and proteasome activity.

Main Results:

  • Roscovitine restored cell surface expression and channel function of F508del-CFTR.
  • The corrective effect was independent of CDK inhibition, unlike other CDK inhibitors tested.
  • Roscovitine inhibits the ER quality control (ERQC) calnexin pathway and proteasome activity.

Conclusions:

  • Roscovitine corrects F508del-CFTR defects through two synergistic, CDK-independent mechanisms.
  • It prevents ERQC interaction and degradation of F508del-CFTR.
  • Roscovitine shows promise as a pharmacological therapy for cystic fibrosis.

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