A posttranslational modification code for CFTR maturation is altered in cystic fibrosis

Sci Signal. 2019 Jan 1;12(562):eaan7984. doi: 10.1126/scisignal.aan7984.

Abstract

The multistep process regulating the maturation of membrane proteins in the endoplasmic reticulum (ER) and the secretory pathway is disrupted in many protein misfolding disorders. Mutations in the ion channel CFTR that impair its folding and subsequent localization to the plasma membrane cause cystic fibrosis (CF), an inherited and eventually lethal disease that impairs the function of multiple organs, mostly the lungs. Here, we found that proper maturation of CFTR is dependent on cross-talk between phosphorylation and methylation events in the regulatory insertion (RI) element of the protein. Manipulating these posttranslational modifications (PTMs) prevented the maturation of wild-type CFTR and instead induced its degradation by ER quality control systems. Deletion of Phe508 (ΔF508), the most prevalent mutation in CF, and other mutations in CFTR that impair its trafficking, such as N1303K, also led to quantitative and qualitative PTM changes that prevented the maturation of misfolded CFTR. Further analysis revealed that a wild-type CFTR-like PTM pattern and function was restored in ΔF508 CFTR when cells were cultured at 28°C but only in the presence of the kinase CK2α. Furthermore, the ability to replicate this PTM pattern predicted the efficacy of treatments in restoring ΔF508 CFTR activity. Accordingly, evaluation of patient information revealed that point mutations of several of the modification sites are associated with clinical CF. These findings identify a minimal quantitative and qualitative PTM code for CFTR maturation that distinguishes correctly folded from misfolded CFTR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cell Line
  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Mutation*
  • Phosphorylation
  • Protein Folding
  • Protein Processing, Post-Translational*
  • Sequence Deletion*
  • Sequence Homology, Amino Acid
  • Sequence Homology, Nucleic Acid

Substances

  • cystic fibrosis transmembrane conductance regulator delta F508
  • Cystic Fibrosis Transmembrane Conductance Regulator