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Open Access Publications from the University of California

Discovery of ubiquitin ligases involved in cytoplasmic quality control

  • Author(s): Heck, Jarrod Wesley
  • et al.

Selective degradation of non-native proteins by cytoplasmic quality control (CQC) mechanisms is at the heart of many misfolded protein disorders. The first line of defense is the molecular chaperone network that binds to misfolded proteins and prevents them from engaging in deleterious interactions with the surrounding environment. Degradation by the ubiquitin proteasome system is a main avenue for eliminating these misfolded proteins. How the chaperone network and the ubiquitination machinery are working together in the cytoplasm to accomplish this feat is only beginning to be understood. These studies have discovered two ubiquitin ligases that are responsible for ubiquitinating and promoting the degradation of cytoplasmic misfolded proteins. These two ligases are Ubr1 and San1. Ubr1 is the first cytoplasmic ligase to be discovered to carry out quality control in this compartment in S. cerevisiae. San1 is a nuclear quality control ligase, and its discovered role in CQC highlights a previously unknown pathway for degrading cytoplasmic misfolded proteins. Both ubiquitin ligases function in a chaperone dependent manner. San1 requires chaperones for transport of misfolded proteins to the nucleus where it is believed it then ubiquitinates its substrates directly. Ubr1 more directly utilizes the chaperones for to facilitate ubiquitination. The chaperone networks of Hsp70 and Hsp90 were required for degradation and ubiquitination of CQC substrates. The Hsp70 cochaperones, Ydj1 and Sse1, were found to also be required for elimination of CQC substrates; however, other cochaperones previously found to be involved in CQC were not. This suggests that the framework for CQC is built upon the Hsp70 and Hsp90 machines, and the cochaperones modulate their activity by providing substrate specificity and recruitment of certain UPS factors to promote degradation. Additionally, Ubr1 is able to ubiquitinate insoluble CQC substrates, but requires the activity of Hsp70, Ydj1 and Sse1 to do so; indicating that chaperone function is not merely relegated to keeping misfolded proteins soluble, but is needed for presentation of misfolded substrate to the ubiquitin ligase. The E3 ligase Ubr1 is highly conserved across eukaryotes, from yeast to humans, and the knowledge gained of its role in chaperone dependent CQC will impact future studies of misfolded protein diseases

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