Correctors Rescue CFTR Mutations in Nucleotide-Binding Domain 1 (NBD1) by Modulating Proteostasis

Miquéias Lopes-Pacheco, Inna Sabirzhanova, Daniele Rapino, Marcelo M. Morales, William B. Guggino, Liudmila Cebotaru

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


We evaluated whether small molecule correctors could rescue four nucleotide-binding domain 1 (NBD1) mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (A455E, S492F, ΔI507, and R560T). We first transfected Cos-7 cells (green monkey kidney cells) with A455E, S492F, ΔI507, or R560T and created HEK-293 (human embryonic kidney cells) cell lines stably expressing these CFTR mutations. The mutants showed lowered protein expression, instability at physiological temperature, and rapid degradation. After treatment with correctors CFFT-002, CFFT-003, C3, C4, and/or C18, the combination of C18+C4 showed the most correction and resulted in increased CFTR residing in the plasma membrane. We found a profound decrease in binding of CFTR to histone deacetylases (HDAC) 6 and 7 and heat shock proteins (Hsps) 27 and 40. Silencing Hsp27 or 40 rescued the mutants, but no additional amount of CFTR was rescued when both proteins were knocked down simultaneously. Thus, CFTR mutations in NBD1 can be rescued by a combination of correctors, and the treatment alters the interaction between mutated CFTR and the endoplasmic reticulum machinery.

Original languageEnglish (US)
Pages (from-to)493-505
Number of pages13
Issue number6
StatePublished - Mar 15 2016


  • correctors
  • cystic fibrosis
  • mutagenesis
  • protein misfolding
  • proteostasis network

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry


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