Cytoplasmic protein quality control degradation mediated by parallel actions of the E3 ubiquitin ligases Ubr1 and San1

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-01, Vol.107 (3), p.1106-1111
• Main Authors: Heck, Jarrod W, Cheung, Samantha K, Hampton, Randolph Y
• Format: Article
• Language: English
• Subjects: Antibodies; Biochemistry; Biological Sciences; Cells; Cytoplasm; Cytoplasm - metabolism; Cytosol; Ethanol; Immunoblotting; Misfolded proteins; Plasmids; Protein folding; Proteins; Quality assurance; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; Studies; Ubiquitin-Protein Ligases - metabolism; Ubiquitins; Yeast; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0910591107

Eukaryotic cells maintain proteostasis by quality control (QC) degradation. These pathways can specifically target a wide variety of distinct misfolded proteins, and so are important for management of cellular stress. Although a number of conserved QC pathways have been described in yeast, the E3 ligases responsible for cytoplasmic QC are unknown. We now show that Ubr1 and San1 mediate chaperone-dependent ubiquitination of numerous misfolded cytoplasmic proteins. This action of Ubr1 is distinct from its role in the "N-end rule." In this capacity, Ubr1 functions to protect cells from proteotoxic stresses. Our phenotypic and biochemical studies of Ubr1 and San1 indicate that two strategies are employed for cytoplasmic QC: chaperone-assisted ubiquitination by Ubr1 and chaperone-dependent delivery to nuclear San1. The broad conservation of Ubr ligases and the relevant chaperones indicates that these mechanisms will be important in understanding both basic and biomedical aspects of cellular proteostasis.