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Hul5 HECT ubiquitin ligase plays a major role in the ubiquitylation and turnover of cytosolic misfolded proteins.

Nature cell biology | Nov 3, 2011

http://www.ncbi.nlm.nih.gov/pubmed/21983566

Cellular toxicity introduced by protein misfolding threatens cell fitness and viability. Failure to eliminate these polypeptides is associated with numerous aggregation diseases. Several protein quality control mechanisms degrade non-native proteins by the ubiquitin-proteasome system. Here, we use quantitative mass spectrometry to demonstrate that heat-shock triggers a large increase in the level of ubiquitylation associated with misfolding of cytosolic proteins. We discover that the Hul5 HECT ubiquitin ligase participates in this heat-shock stress response. Hul5 is required to maintain cell fitness after heat-shock and to degrade short-lived misfolded proteins. In addition, localization of Hul5 in the cytoplasm is important for its quality control function. We identify potential Hul5 substrates in heat-shock and physiological conditions to reveal that Hul5 is required for ubiquitylation of low-solubility cytosolic proteins including the Pin3 prion-like protein. These findings indicate that Hul5 is involved in a cytosolic protein quality control pathway that targets misfolded proteins for degradation.

Pubmed ID: 21983566 RIS Download

Mesh terms: Cytosol | Heat-Shock Proteins | Heat-Shock Response | Mass Spectrometry | Molecular Chaperones | Prions | Protein Folding | Protein Processing, Post-Translational | Saccharomyces cerevisiae | Saccharomyces cerevisiae Proteins | Time Factors | Ubiquitin-Protein Ligases | Ubiquitination

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Associated grants

  • Agency: Canadian Institutes of Health Research, Id:

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