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Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes

Manu Sharma1, Francesca Pampinella, Csilla Nemes

  • 1Hospital for Sick Children, Program in Cell and Lung Biology, 555 University Ave., Toronto, Ontario M5G 1X8, Canada.

The Journal of Cell Biology
|March 10, 2004
PubMed

Insights

Misfolded cystic fibrosis transmembrane conductance regulator (CFTR) proteins are targeted for degradation via ubiquitination and lysosomal pathways. This study reveals how protein folding impacts CFTR trafficking and degradation, offering insights into CF pathogenesis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Protein Degradation

Background:

  • Misfolded membrane proteins pose challenges for cellular quality control.
  • Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations can lead to protein misfolding and disease.
  • Understanding the degradation pathways of misfolded proteins is crucial for cellular health.

Purpose of the Study:

  • To investigate the degradation mechanism of misfolded CFTR from the cell surface.
  • To determine how the folding state of CFTR influences its post-endocytic trafficking.
  • To establish a link between ubiquitination and lysosomal degradation of misfolded CFTR.

Main Methods:

  • Utilized mutant CFTRs with conformational defects.
  • Analyzed post-endocytic trafficking and lysosomal targeting.
  • Investigated protein ubiquitination and association with endosomal sorting machinery components.
  • Manipulated folding defects and ubiquitin-activating enzyme levels.

Main Results:

  • CFTR folding state dictates post-endocytic trafficking.
  • Misfolded CFTR is ubiquitinated, preventing recycling and promoting lysosomal degradation.
  • Stabilization of mutant CFTR achieved by rescuing folding defects or down-regulating E1 ubiquitin-activating enzyme.
  • Mutant CFTRs associate with components of the ubiquitin-dependent endosomal sorting machinery.

Conclusions:

  • A functional link exists between ubiquitination and lysosomal degradation of cell surface misfolded CFTR.
  • This pathway represents a novel cellular mechanism in Cystic Fibrosis pathogenesis.
  • A paradigm for plasma membrane protein quality control involving ubiquitination and endosomal sorting is proposed.

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