Regulating regulators to survive nutrient limitation: Lessons from yeast

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Saccharomyces cerevisiae serves our society as a pivotal model organism in resolving fundamental questions in eukaryotic biology, and in its capacity to convert fermentable sugars, such as glucose, into ethanol and CO2 in the baking, beverage and bio-ethanol industries. While yeast prefers this fermentative metabolism to generate energy, it can efficiently use non-fermentable carbon sources, like ethanol, when glucose is depleted. During commercially important alcoholic fermentations, yeast commonly experience glucose depletion and increasing levels of ethanol, which negatively impacts the yeast's physiology and metabolism, which in turn decreases fermentation efficiency. Our overarching research goal is to understand the mechanisms that govern the adaptation of yeast to fermentation stresses, and to ultimately use this information to develop technologies to increase capacity in the fermentation industry. When glucose is abundant, the genes needed for fermentative growth are actively expressed, while those needed to metabolize non-fermentable carbon sources, like ethanol, are inhibited. This transcriptional regulation reverses when glucose is depleted, and ethanol is the sole carbon source. Similarly, the abundance, activity and intracellular localization of proteins can also be regulated by the available carbon source. Despite the identification and characterization of several regulatory proteins and signaling mechanisms that govern the adaptation of yeast to glucose depletion, the detailed aspects of transcriptional adaptation and the turnover of target proteins remain unresolved. We recently showed the Vid30 protein complex (Vid30c), an E3 ubiquitin ligase that links ubiquitin to target proteins destined for destruction, impacts the signaling mechanisms that govern fermentative metabolism, affects the transcriptional regulation of glucose repressed genes, and enables the degradation of the hexose transporters in response to glucose depletion. The molecular mechanisms used by Vid30c to mediate these specific events are currently unknown. Thus, the objectives of the proposed research are to characterize the impact of Vid30c on glucose-regulated gene expression and to identify and characterize its direct regulation of specific target proteins in response to carbon availability. We will use a combination of yeast genetic, molecular and cellular biology approaches to achieve these goals. The role of Vid30c in the expression, abundance, posttranslational modification, and subcellular localization of transcription factors and signaling proteins will provide further fundamental insight into the regulatory mechanisms that govern regulators in response to carbon availability. This information will generate a better understanding of commercial fermentations and could lead to the development of strategies to increase the fermentation efficiency of this commercially important organism.