Cdc48 plays a crucial role in redox homeostasis through dynamic reshaping of its interactome during early stationary phase.
Most microbial cells on earth predominantly exist in non-proliferating, dormant conditions, such as the stationary state. The stationary phase is a crucial stage during the cellular lifespan, which requires homeostatic rewiring for long-term viability and rapid responses to environmental changes. Here, we show that entry to the stationary phase in ... yeast is accompanied by increased cytosolic and mitochondrial oxidation, imposing stress on the proteostasis network. We establish a functional link between redox and protein homeostasis, mediated by a key protein quality control member, Cdc48/p97/VCP. Comparative proteomic analysis of post-mitotic yeast cells reveals that while the global proteome remains largely stable during the first stages of stationary phase, the Cdc48 interactome undergoes significant remodeling, including altered interactions with antioxidants and its cofactors Shp1/Ubx1 and Ubx2. To challenge yeast Cdc48's capacity as a redox-switch protein during the early stages of the stationary phase, we utilized redox proteomics to map changes in reversible oxidation modification on Cdc48's cysteines upon entry to the stationary phase. We revealed the temporal and reversible oxidation of Cdc48-Cys115 as a key regulatory event essential for stationary-phase survival and interactome modulation. Cys115-to-serine mutation significantly reduced longevity and increased oxidative stress sensitivity, correlating with disrupted interactions between Cdc48 and antioxidants, and cofactor Shp1, specifically with the phosphorylated form of Shp1. Taken together, these findings identify a new thiol switch protein in the protein degradation pathway, while further defining novel roles for Cdc48 in reshaping the proteome during the yeast stationary phase.
Mesh Terms:
Homeostasis, Intracellular Signaling Peptides and Proteins, Mitochondria, Oxidation-Reduction, Oxidative Stress, Proteome, Proteomics, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Valosin Containing Protein
Homeostasis, Intracellular Signaling Peptides and Proteins, Mitochondria, Oxidation-Reduction, Oxidative Stress, Proteome, Proteomics, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Valosin Containing Protein
Redox Biol
Date: Jul. 01, 2025
PubMed ID: 40359616
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