Metabolomics analysis of an AAA-ATPase Cdc48-deficient yeast strain

The ubiquitin-specific chaperone AAA-ATPase Cdc48 and its orthologs p97/valosin-containing protein (VCP) in mammals play crucial roles in regulating numerous intracellular pathways via segregase activity, which separates polyubiquitinated targets from membranes or binding partners. Interestingly, high-throughput experiments show that a vast number of metabolic enzymes are modified with ubiquitin. Therefore, Cdc48 may regulate metabolic pathways, for example by acting on the polyubiquitin chains of metabolic enzymes; however, the role of Cdc48 in metabolic regulation remains largely unknown. To begin to analyze the role of Cdc48 in metabolic regulation in yeast, we performed a metabolomics analysis of temperature-sensitive cdc48-3 mutant cells. We found that the amount of metabolites in the glycolytic pathway was altered. Moreover, the pool of nucleotides, as well as the levels of metabolites involved in the tricarboxylic acid cycle and oxidative phosphorylation, increased, whereas the pool of amino acids decreased. These results suggest the involvement of Cdc48 in metabolic regulation in yeast. In addition, because of the roles of p97/VCP in regulating multiple cellular pathways, its inhibition is being considered as a promising anticancer drug target. We propose that the metabolomics study of Cdc48-deficient yeast will be useful as a complement to p97/VCP-related pathological and therapeutic studies.