The Yeast Ubr1 Ubiquitin Ligase Participates in a Prominent Pathway That Targets Cytosolic Thermosensitive Mutants for Degradation

G3: Genes, Genomes, Genetics

Sophie A. Comyn¹  Jason M. Winget¹  Nancy N. Fang¹  Alex H. M. Ng¹  Thibault Mayor¹  Farzin Khosrow-Khavar¹ 

[1] Department of Biochemistry and Molecular Biology, Center for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada Department of Biochemistry and Molecular Biology, Center for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada Department of Biochemistry and Molecular Biology, Center for High-Throughput Biology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada

关键词: protein quality control;    misfolding;    ubiquitin proteasome system;    E3 ligase;    Ubr1;    San1;    Saccharomyces cerevisiae;   

DOI  :  10.1534/g3.111.001933

学科分类：生物科学（综合）

来源: Genetics Society of America

【 摘 要 】

Mutations causing protein misfolding and proteolysis are associated with many genetic diseases. The degradation of these aberrant proteins typically is mediated by protein-quality control pathways that recognize misfolded domains. Several E3 ubiquitin ligases have been shown to target cytosolic misfolded proteins to the proteasome. In this study, we characterized a panel of more than 20 cytosolic thermosensitive mutants from six essential genes in Saccharomyces cerevisiae. These wild-type proteins are stable at restrictive temperature. In contrast, we found that a large portion of the mutants is degraded at nonpermissive temperature in a proteasome-dependent manner. Approximately one-third of the assessed unstable mutants are targeted by the Ubr1 ubiquitin ligase. In two cases, efficient degradation of the thermosensitive mutants is abrogated in the absence of Ubr1 alone, whereas in a third case it is reliant on the dual deletion of Ubr1 and the nuclear E3 ligase San1. We found that the impairment of the degradation of these quality control substrates at the restrictive temperature is associated with the suppression of thermosensitive phenotype. This study confirms that Ubr1 plays an important role in the degradation of cytosolic misfolded proteins and indicates that degradation mediated by protein quality control is a major cause for the conditional lethality of mutated essential genes.

【 授权许可】

Unknown