A Novel Approach to Recovery of Function of Mutant Proteins by Slowing Down Translation

From the Department of Biochemistry, Boston University Medical School, Boston, Massachusetts 02118.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2012; 287(41):34264-72. DOI: 10.1074/jbc.M112.397307
Source: PubMed


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.

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Available from: Hermann Bihler, Jul 18, 2014
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