Combination of correctors rescues CFTR transmembrane-domain mutants by mitigating their interactions with proteostasis

Miquéias Lopes-Pacheco, Clément Boinot, Inna Sabirzhanova, Daniele Rapino, Liudmila Cebotaru

Research output: Contribution to journalArticlepeer-review

Abstract

Background/Aims: Premature degradation of mutated cystic fibrosis transmembrane conductance regulator (CFTR) protein causes cystic fibrosis (CF), the commonest Mendelian disease in Caucasians. Despite recent advances in precision medicines for CF patients, many CFTR mutants have not been characterized and the effects of these new therapeutic approaches are still unclear for those mutants. Methods: Cells transfected or stably expressing four CFTR transmembrane-domain mutants (G85E, E92K, L1077P, and M1101K) were used to: 1) characterize the mutants according to their protein expression, thermal sensitivity, and degradation pathways; 2) evaluate the effects of correctors in rescuing them; and 3) explore the effects of correctors on CFTR interactions with proteostasis components. Results: All four mutants exhibited lower protein expression than did wild type-CFTR, and they were degraded by proteasomes and aggresomes. At low temperature, only cells expressing the mutants L1077P and M1101K exhibited increased CFTR maturation. Co-administration of C4 and C18 showed the greatest effect, restoring functional expression and partial stability of CFTR bearing E92K, L1077P, or M1101K at the cell surface. However, this treatment was inefficient in rectifying the defect of CFTR bearing G85E. Correctors rescued CFTR mutants by reducing their interactions with proteostasis components associated with protein retention in the endoplasmic reticulum and ubiquitination. Conclusion: Co-administration of C4 and C18 rescued CFTR transmembrane-domain mutants by remodeling the CFTR interactome.

Original languageEnglish (US)
Pages (from-to)2194-2210
Number of pages17
JournalCellular Physiology and Biochemistry
Volume41
Issue number6
DOIs
StatePublished - Jun 1 2017

Keywords

  • CFTR Mutants
  • Cystic fibrosi
  • Electrophysiology
  • Heat shock protein
  • Intracellular trafficking
  • Membrane-spanning
  • Precision medicine
  • Protein folding
  • Proteostasis network

ASJC Scopus subject areas

  • Physiology

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