To sustain growth in changing nutrient conditions, cells reorganize outputs of metabolic networks and appropriately reallocate resources. My PhD research broadly focused on identifying novel signaling regulators that control such adaptations. While reversible protein phosphorylation is known to regulate these adaptations, the role of protein phosphatases in this process is less explored. My thesis investigates how phosphatases facilitate metabolic adaptation to glucose depletion. Using a Saccharomyces cerevisiae deletion screen, we identified the PP2A-like phosphatase Ppg1 as required for appropriate carbon allocations towards gluconeogenic outputs— trehalose, glycogen, UDP-glucose, UDP-GlcNAc—after glucose depletion. This Ppg1 function is mediated via regulation of the assembly of the Far complex—a multi-subunit complex that tethers to the ER and mitochondrial outer membranes, forming localized signaling hubs. We find that the Far complex assembly is Ppg1 catalytic activity-dependent and requires dephosphorylation of multiple ser/thr residues on Far11. The fully assembled Far complex is needed to maintain gluconeogenic outputs after glucose depletion. Additionally, extracellular glucose availability regulates Far complex amounts, ensuring metabolic regulation specifically in glucose-depleted phase. Overall, this Ppg1-mediated Far complex assembly and Ppg1-Far complex dependent control of gluconeogenic outputs enables adaptive growth under glucose depletion. Future research is required to uncover specific signaling events controlled by the Ppg1-Far complex assembly that drive these adaptive responses. Ultimately, my thesis reveals how protein dephosphorylation is key to assembling localized signaling hubs that modulate carbon flux, opening new avenues for understanding metabolic adaptation in fluctuating nutrient environments.

Publications:

Niphadkar, S., Karinje, L. and Laxman, S., 2024. The PP2A-like phosphatase Ppg1 mediates assembly of the Far complex to balance gluconeogenic outputs and enables adaptation to glucose depletion. PLoS Genetics, 20(3), p.e1011202.

Vengayil, V., Niphadkar, S., Adhikary, S., Varahan, S. and Laxman, S., 2024. The deubiquitinase Ubp3/Usp10 constrains glucose-mediated mitochondrial repression via phosphate budgeting. Elife.