F508del-CFTR rescue: a matter of cell stress response

Curr Pharm Des. 2013;19(19):3476-96. doi: 10.2174/13816128113199990317.


Cystic fibrosis (CF) is a common inherited fatal disease affecting 70,000 people worldwide, with a median predicted age of survival of approximately 38 years. The deletion of Phenylalanine in position 508 of the Cystic Fibrosis Transmembrane conductance Regulator (F508del-CFTR) is the most common mutation in CF patients: the deleted protein, not properly folded, is degraded. To date no commercial drugs are available. Low temperature, some osmolytes and conditions able to induce heat shock protein 70 (Hsp70) expression and heat shock cognate 70 (Hsc70) inhibition result in F508del-CFTR rescue, hence restoring its physiological function: this review sheds light on the correlation between these several evidences. Interestingly, all these approaches have a role in the cell stress response (CSR), a set of cell reactions to stress. In addition, unpredictably, F508del-CFTR rescue has to be considered in the frame of CSR: entities that induce - or are induced during - the CSR are, in general, also able to correct trafficking defect of CFTR. Specifically, the low temperature induces, by definition, a CSR; osmolytes, such as glycerol and trimethylamine N-oxide (TMAO), are products of the CSR; pharmacological correctors, such as Matrine and 4-phenylbutirric acid (4PBA), down-regulate the constitutive Hsc70 in favor of an up-regulation of the inducible chaperone Hsp70, another component of the CSR. The identification of a common mechanism of action for different types of correctors could drive the discovery of new active molecules in CF, overcoming methods clinically inapplicable, such as the low temperature.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alkaloids / administration & dosage
  • Alkaloids / pharmacology
  • Alkaloids / therapeutic use
  • Animals
  • Cell Membrane / metabolism
  • Cold Temperature
  • Curcumin / administration & dosage
  • Curcumin / pharmacology
  • Curcumin / therapeutic use
  • Cystic Fibrosis / drug therapy
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress* / drug effects
  • Endoplasmic Reticulum Stress* / genetics
  • HSP70 Heat-Shock Proteins / antagonists & inhibitors
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism*
  • Humans
  • Matrines
  • Models, Molecular
  • Molecular Targeted Therapy
  • Phenylbutyrates / administration & dosage
  • Phenylbutyrates / pharmacology
  • Phenylbutyrates / therapeutic use
  • Protein Interaction Domains and Motifs
  • Protein Transport / drug effects
  • Quinolizines / administration & dosage
  • Quinolizines / pharmacology
  • Quinolizines / therapeutic use


  • Alkaloids
  • HSP70 Heat-Shock Proteins
  • Phenylbutyrates
  • Quinolizines
  • cystic fibrosis transmembrane conductance regulator delta F508
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • 4-phenylbutyric acid
  • Curcumin
  • Matrines