Breadth and Specificity in Pleiotropic Protein Kinase A Activity and Environmental Responses

Kocik, Rachel A; Gasch, Audrey P.

doi:10.3389/fcell.2022.803392

Cited by 3 publications

(6 citation statements)

References 154 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, Ira2 can localize to mitochondria, suggesting that PKA can also localize to this organelle [ 78 ]. In fact, PKA is found at the mitochondria of higher eukaryotes [ 79 ], suggesting that yeast PKA may also localize to the mitochondria. Together, our results suggest that upregulated PKA activity is required for xylose fermentation and can occur via either IRA2 or BCY1 deletion, but deletion of BCY1 produces stronger effects that underscore its higher per-cell rate of xylose fermentation [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth in Saccharomyces cerevisiae

et al. 2023

Self Cite

View full text Add to dashboard Cite

Organisms have evolved elaborate physiological pathways that regulate growth, proliferation, metabolism, and stress response. These pathways must be properly coordinated to elicit the appropriate response to an ever-changing environment. While individual pathways have been well studied in a variety of model systems, there remains much to uncover about how pathways are integrated to produce systemic changes in a cell, especially in dynamic conditions. We previously showed that deletion of Protein Kinase A (PKA) regulatory subunit BCY1 can decouple growth and metabolism in Saccharomyces cerevisiae engineered for anaerobic xylose fermentation, allowing for robust fermentation in the absence of division. This provides an opportunity to understand how PKA signaling normally coordinates these processes. Here, we integrated transcriptomic, lipidomic, and phospho-proteomic responses upon a glucose to xylose shift across a series of strains with different genetic mutations promoting either coupled or decoupled xylose-dependent growth and metabolism. Together, results suggested that defects in lipid homeostasis limit growth in the bcy1Δ strain despite robust metabolism. To further understand this mechanism, we performed adaptive laboratory evolutions to re-evolve coupled growth and metabolism in the bcy1Δ parental strain. The evolved strain harbored mutations in PKA subunit TPK1 and lipid regulator OPI1, among other genes, and evolved changes in lipid profiles and gene expression. Deletion of the evolved opi1 gene partially reverted the strain’s phenotype to the bcy1Δ parent, with reduced growth and robust xylose fermentation. We suggest several models for how cells coordinate growth, metabolism, and other responses in budding yeast and how restructuring these processes enables anaerobic xylose utilization.

show abstract

Section: Discussionmentioning

confidence: 99%

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth in Saccharomyces cerevisiae

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…PKA can be directed to subcellular targets in higher eukaryotes via A-kinase anchoring proteins (AKAP) that bind to and direct localization of PKA (110). While yeast do not possess orthologs of AKAPs, functional analogs have been proposed including Bcy1 itself (89,111,112). Anaerobic xylose growth and metabolism may be decoupled in bcy1∆ strains via disrupted subcellular localization and substrate interactions of PKA that are coordinated by Bcy1.…”

Section: Discussionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted December 29, 2022. ; https://doi.org/10.1101/2022.12.28.522075 doi: bioRxiv preprint mitochondria, suggesting that PKA can also localize to this organelle (88). In fact, PKA is found at the mitochondria of higher eukaryotes (89), suggesting that yeast PKA may also localize to the mitochondria. Together, our results suggest that upregulated PKA activity is required for xylose fermentation and can occur via either IRA2 or BCY1 deletion, but deletion of BCY1 produces stronger effects that underscore its higher per-cell rate of xylose fermentation (32).…”

Section: Discussionmentioning

confidence: 99%

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth inSaccharomyces cerevisiae

Wagner

Nightingale

Jen

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Organisms have evolved elaborate physiological pathways that regulate growth, proliferation, metabolism, and stress response. These pathways must be properly coordinated to elicit the appropriate response to an ever-changing environment. While individual pathways have been well studied in a variety of model systems, there remains much to uncover about how pathways are integrated to produce systemic changes in a cell, especially in dynamic conditions. We previously showed that deletion of Protein Kinase A (PKA) regulatory subunit BCY1 can decouple growth and metabolism in Saccharomyces cerevisiae engineered for anaerobic xylose fermentation, allowing for robust fermentation in the absence of division. This provides an opportunity to understand how PKA signaling normally coordinates these processes. Here, we integrated transcriptomic, lipidomic, and phosphor-proteomic responses upon a glucose to xylose shift across a series of strains with different genetic mutations promoting either coupled or decoupled xylose-dependent growth and metabolism. Together, results suggested that defects in lipid homeostasis limit growth in the bcy1Δ strain despite robust metabolism. To further understand this mechanism, we performed adaptive laboratory evolutions to re-evolve coupled growth and metabolism in the bcy1Δ parental strain. Genetic mutations in PKA subunit TPK1 and lipid regulator OPI1, among other genes underscored a role for lipid homeostasis, which was further supported by evolved changes in lipid profiles and gene expression. We suggest several models for how cells coordinate growth, metabolism, and other responses in budding yeast and how restructuring these processes enables anaerobic xylose utilization.

show abstract

“…Higher eukaryotes have a variety of A-kinase anchoring proteins (AKAPs) that bind the regulatory subunit to control the PKA’s subcellular localization [ 135 ]. AKAPs have tissue-specific expression and regulate PKA–substrate interactions [ 135 , 136 , 137 , 138 , 139 , 140 ]. They have also been described to form signalosomes, which produce micro-environments of PKA, PKA substrates, PDEs, and/or other upstream components of the PKA pathway [ 141 , 142 ].…”

Section: Key Regulators That Govern Physiological Pathways Rewired Fo...mentioning

confidence: 99%

“…They have also been described to form signalosomes, which produce micro-environments of PKA, PKA substrates, PDEs, and/or other upstream components of the PKA pathway [ 141 , 142 ]. This is predicted to bring PKA in contact with the substrates and quickly and dynamically regulate PKA activity via cAMP abundance [ 139 , 141 , 142 , 143 , 144 , 145 ]. While yeast does not possess recognizable AKAP orthologs, several functional analogs have been proposed [ 146 , 147 , 148 ].…”

Section: Key Regulators That Govern Physiological Pathways Rewired Fo...mentioning

confidence: 99%

Advances in S. cerevisiae Engineering for Xylose Fermentation and Biofuel Production: Balancing Growth, Metabolism, and Defense

Wagner

Gasch

2023

JoF

Self Cite

View full text Add to dashboard Cite

Genetically engineering microorganisms to produce chemicals has changed the industrialized world. The budding yeast Saccharomyces cerevisiae is frequently used in industry due to its genetic tractability and unique metabolic capabilities. S. cerevisiae has been engineered to produce novel compounds from diverse sugars found in lignocellulosic biomass, including pentose sugars, like xylose, not recognized by the organism. Engineering high flux toward novel compounds has proved to be more challenging than anticipated since simply introducing pathway components is often not enough. Several studies show that the rewiring of upstream signaling is required to direct products toward pathways of interest, but doing so can diminish stress tolerance, which is important in industrial conditions. As an example of these challenges, we reviewed S. cerevisiae engineering efforts, enabling anaerobic xylose fermentation as a model system and showcasing the regulatory interplay’s controlling growth, metabolism, and stress defense. Enabling xylose fermentation in S. cerevisiae requires the introduction of several key metabolic enzymes but also regulatory rewiring of three signaling pathways at the intersection of the growth and stress defense responses: the RAS/PKA, Snf1, and high osmolarity glycerol (HOG) pathways. The current studies reviewed here suggest the modulation of global signaling pathways should be adopted into biorefinery microbial engineering pipelines to increase efficient product yields.

show abstract

Breadth and Specificity in Pleiotropic Protein Kinase A Activity and Environmental Responses

Cited by 3 publications

References 154 publications

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth in Saccharomyces cerevisiae

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth in Saccharomyces cerevisiae

PKA regulatory subunit Bcy1 couples growth, lipid metabolism, and fermentation during anaerobic xylose growth inSaccharomyces cerevisiae

Advances in S. cerevisiae Engineering for Xylose Fermentation and Biofuel Production: Balancing Growth, Metabolism, and Defense

Contact Info

Product

Resources

About