The role of Yca1 in Proteostasis. Yca1 Regulates the Composition of the Insoluble Proteome.

Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Journal of proteomics (Impact Factor: 3.89). 01/2013; 81. DOI: 10.1016/j.jprot.2013.01.014
Source: PubMed


Proteostasis, the process of balancing protein production with protein degradation is vital to normal cell function. Defects within the mechanisms that control proteostasis lead to increased content of a specialized insoluble protein fraction that forms dense aggregates within the cell. We have previously implicated the S. cerevisiae metacaspase Yca1 as an active participant in maintaining proteostasis, whereby Yca1 acts to limit aggregate content. Here, we further characterized the proteostasis role of Yca1 by conducting proteomic analysis of the insoluble protein fraction in wildtype and yca1 knockout cells, under normal and heat stressed conditions. Our findings suggest that the composition of insoluble protein fraction is non-specific and comprises a wide array of protein species rather than a limited repertoire of aggregate susceptible proteins or peptides. Interestingly, the loss of Yca1 led to a significant decrease of proteins that control ribosome biogenesis and protein synthesis within the insoluble fraction, indicating that the cell may invoke a compensatory mechanism to limit protein production during stress, a feature dependent on Yca1 activity. Finally, we noted that protein degradation factors such as Cdc48 co-localize with Yca1 to the insoluble fraction, supporting the hypothesis that Yca1 may act primarily to dissolve or reduce accumulated aggregates.

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    • "On the other hand, the ability of metacaspase to both promote and antagonize different cell cycle checkpoints has been demonstrated, representing an early form of the proliferation/ differentiation regulatory activity exhibited by metazoan caspases [16]. YCA1 also contributes to the fitness and adaptability of growing yeast through clearance of insoluble protein aggregates [17] [18] and has been implicated in the regulation of antioxidant status and mitochondrial respiration [15] [19] [20]. The concept of non-apoptotic roles of metacaspase has been expanded in our previous work in which we have performed a comparative analysis between wild type and Δyca1 cells using combined proteomic and metabolomic approach. "
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    ABSTRACT: Caspase proteases are responsible for the regulated disassembly of the cell into apoptotic bodies during mammalian apoptosis. Structural homologues of the caspase family (called metacaspases) are involved in programmed cell death in single-cell eukaryotes, yet the molecular mechanisms that contribute to death are currently undefined. Recent evidence revealed that a programmed cell death process is induced by acetic acid (AA-PCD) in Saccharomyces cerevisiae both in the presence and absence of metacaspase encoding gene YCA1. Here, we report an unexpected role for the yeast metacaspase in protein quality and metabolite control. By using an "omics" approach, we focused our attention on proteins and metabolites differentially modulated en route to AA-PCD either in wild type or YCA1-lacking cells. Quantitative proteomic and metabolomic analyses of wild type and Δyca1 cells identified significant alterations in carbohydrate catabolism, lipid metabolism, proteolysis and stress-response, highlighting the main roles of metacaspase in AA-PCD. Finally, deletion of YCA1 led to AA-PCD pathway through the activation of ceramides, whereas in the presence of the gene yeast cells underwent an AA-PCD pathway characterized by the shift of the main glycolytic pathway to the pentose phosphate pathway and a proteolytic mechanism to cope with oxidative stress. The yeast metacaspase regulates both proteolytic activities through the ubiquitin-proteasome system and ceramide metabolism as revealed by proteome and metabolome profiling of YCA1-knock-out cells during acetic-acid induced programmed cell death. Copyright © 2015 Elsevier B.V. All rights reserved.
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