A novel approach to recovery of function of mutant proteins by slowing down translation

J Biol Chem. 2012 Oct 5;287(41):34264-72. doi: 10.1074/jbc.M112.397307. Epub 2012 Aug 17.

Abstract

Protein homeostasis depends on a balance of translation, folding, and degradation. Here, we demonstrate that mild inhibition of translation results in a dramatic and disproportional reduction in production of misfolded polypeptides in mammalian cells, suggesting an improved folding of newly synthesized proteins. Indeed, inhibition of translation elongation, which slightly attenuated levels of a copepod GFP mutant protein, significantly enhanced its function. In contrast, inhibition of translation initiation had minimal effects on copepod GFP folding. On the other hand, mild suppression of either translation elongation or initiation corrected folding defects of the disease-associated cystic fibrosis transmembrane conductance regulator mutant F508del. We propose that modulation of translation can be used as a novel approach to improve overall proteostasis in mammalian cells, as well as functions of disease-associated mutant proteins with folding deficiencies.

Publication types

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

MeSH terms

  • Animals
  • Cystic Fibrosis Transmembrane Conductance Regulator / biosynthesis*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Green Fluorescent Proteins / biosynthesis*
  • Green Fluorescent Proteins / genetics
  • HeLa Cells
  • Humans
  • Models, Biological*
  • Mutation*
  • Peptide Chain Elongation, Translational*
  • Protein Folding*
  • Rats

Substances

  • CFTR protein, human
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Green Fluorescent Proteins