Seminar

From misfolding to degradation with ubiquitin: a global stress to reveal a novel cytosolic protein quality control pathway

Thibault Mayor, PhD

Cellular toxicity introduced by protein misfolding threatens cell fitness and viability. Failure of eliminating these aberrant polypeptides is associated with numerous aggregation pathologies, like Parkinson's and Huntington's diseases. Several protein quality control mechanisms have evolved in eukaryotic cells to degrade non-native proteins by the ubiquitin proteasome system. Here, we show by using quantitative mass spectrometry that heat-shock triggers a large increase of ubiquitylation associated to misfolding of cytosolic proteins. We discovered that the Hul5 ubiquitin ligase participates in this heat-stress response to degrade misfolded protein. We identified several potential substrates of Hul5 upon heat-shock and in physiological conditions to reveal that Hul5 is important for the ubiquitylation of low solubility cytosolic proteins such as the Pin3 prion-like protein. Together, these findings indicate that the Hul5 HECT ligase is involved in a novel cytosolic protein quality control pathway that targets misfolded proteins for proteolysis.