A novel approach to recovery of function of mutant proteins by slowing down translation.
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.
Department of Biochemistry, Boston University Medical School, Boston, Massachusetts 02118, USA.
Anatoli B
AB
Meriin
Martin
M
Mense
Jeff D
JD
Colbert
Feng
F
Liang
Hermann
H
Bihler
Nava
N
Zaarur
Kenneth L
KL
Rock
Michael Y
MY
Sherman
D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000096:biosynthesis* / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000096:biosynthesis* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D010441:Peptide Chain Elongation, Translational; D017510:Protein Folding; D051381:Rats
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D049452:Green Fluorescent Proteins