Defects in processing and trafficking of the cystic fibrosis transmembrane conductance regulator

William R. Skach

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


Cystic fibrosis (CF) is caused by inherited mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel expressed in epithelial tissues. Most mutations in CF patients result in rapid intracellular degradation of the CFTR protein. While this defect is thought to result from abnormal protein folding, it is unclear how mutant and wild-type (WT) proteins differ in structure, how the cell is able to distinguish these differences, and how the fate of the mutant protein is determined. By examining the initial steps of CFTR assembly into the endoplasmic reticulum (ER) membrane, it has recently been shown that CFTR utilizes two redundant translocation pathways to direct N-terminus folding events. Mutations that block one pathway therefore do not alter transmembrane topology, but rather appear to disrupt intracellular trafficking through perturbations in higher order tertiary structure. These studies suggest that cellular quality control machinery acts at least in part, by monitoring proper interactions between CFTR subdomains. The end. Result of this process is the conversion of misfolded CFTR into a membrane- bound, polyubiquitinated complex. This complex recruits cytosolic degradation machinery to the endoplasmic reticulum membrane where CFTR is degraded as it is extracted from the lipid bilayer. Understanding how cellular machinery mediates this process will be an important step in designing strategies to modify protein folding and degradation in CF and related ion channelopathies.

Original languageEnglish (US)
Pages (from-to)825-831
Number of pages7
JournalKidney International
Issue number3
StatePublished - 2000
Externally publishedYes


  • Biogenesis
  • CFTR
  • Cystic fibrosis
  • Endoplasmic reticulum
  • Ion channel
  • Topology

ASJC Scopus subject areas

  • Nephrology


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