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

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

Authors

  • Fang NN
  • Ng AH
  • Measday V
  • Mayor T

Journal

Nature cell biology

Publication Data

November 3, 2011

Associated Grants

  • Agency: Canadian Institutes of Health Research, Id:

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