From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking

Cell Mol Life Sci. 2017 Jan;74(1):39-55. doi: 10.1007/s00018-016-2387-7. Epub 2016 Oct 3.


CFTR biogenesis starts with its co-translational insertion into the membrane of endoplasmic reticulum and folding of the cytosolic domains, towards the acquisition of a fully folded compact native structure. Efficiency of this process is assessed by the ER quality control system that allows the exit of folded proteins but targets unfolded/misfolded CFTR to degradation. If allowed to leave the ER, CFTR is modified at the Golgi and reaches the post-Golgi compartments to be delivered to the plasma membrane where it functions as a cAMP- and phosphorylation-regulated chloride/bicarbonate channel. CFTR residence at the membrane is a balance of membrane delivery, endocytosis, and recycling. Several adaptors, motor, and scaffold proteins contribute to the regulation of CFTR stability and are involved in continuously assessing its structure through peripheral quality control systems. Regulation of CFTR biogenesis and traffic (and its dysregulation by mutations, such as the most common F508del) determine its overall activity and thus contribute to the fine modulation of chloride secretion and hydration of epithelial surfaces. This review covers old and recent knowledge on CFTR folding and trafficking from its synthesis to the regulation of its stability at the plasma membrane and highlights how several of these steps can be modulated to promote the rescue of mutant CFTR.

Keywords: CFTR; Cystic fibrosis; Endoplasmic reticulum quality control; Folding; Membrane stability; Trafficking.

Publication types

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

MeSH terms

  • Animals
  • Cell Membrane / genetics
  • Cell Membrane / metabolism*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator / analysis
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Endocytosis
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism
  • Humans
  • Protein Folding*
  • Protein Interaction Maps
  • Protein Processing, Post-Translational
  • Protein Transport
  • Sequence Deletion


  • Cystic Fibrosis Transmembrane Conductance Regulator