THE DEUBIQUITINASE UBP6 IS REQUIRED FOR DEGRADING MISFOLDED PROTEINS

Abstract

The quality control of intracellular proteins is achieved by degrading misfolded proteins which cannot be refolded by molecular chaperones. In eukaryotes, such degradation is handled primarily by the ubiquitin-proteasome pathway. It remains unclear, however, whether and how this process deploys various deubiquitinases, enzymes that trim ubiquitin chains. To address this question, we screened deletions of deubiquitinase genes in Saccharomyces cerevisiae for their effects on protein quality control. Nearly half of these deletions, including Δubp6, slow the removal of misfolded proteins, whereas none of the rest deletions accelerate this process significantly. We further focused on Δubp6 because it was previously speculated to augment quality control degradation. We confirmed that Ubp6 is required for efficiently degrading misfolded proteins in cytosol and nucleus. Meanwhile, the clearance of misfolded endoplasmic reticulum proteins and the degradation of folded cytosolic and nuclear proteins are not compromised by UBP6 deletion. The delay in cytosolic and nuclear quality control after deleting UBP6 is correlated with the depletion of free ubiquitins and a decrease in protein ubiquitination in this mutant.