The PP2A-like phosphatase Ppg1 mediates assembly of the Far complex to balance gluconeogenic outputs and adapt to glucose depletion

Abstract

To sustain growth in changing nutrient conditions, cells reorganize outputs of metabolic networks and appropriately reallocate resources. Signaling by reversible protein phosphorylation can control such metabolic adaptations. In contrast to kinases, the functions of phosphatases that enable metabolic adaptation as glucose depletes are poorly studied. Using a Saccharomyces cerevisiae deletion screen, we identified the requirement of PP2A-like phosphatase Ppg1 for appropriate carbon allocations towards gluconeogenic outputs - trehalose, glycogen, UDP-glucose, UDP-GlcNAc - specifically after glucose depletion. This homeostatic 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 as localized signaling hubs. We show that the Far complex assembly is Ppg1 catalytic activity-dependent. The assembled Far complex is required to maintain gluconeogenic outputs after glucose depletion. Glucose in turn regulates Far complex abundance. This Ppg1-mediated Far complex assembly, and dependent control of gluconeogenic outputs enhances adaptive growth under glucose depletion. Our study illustrates how protein dephosphorylation is required for the assembly of a multi-protein scaffold present in localized cytosolic pools, to thereby enable cells metabolically adapt to nutrient fluctuations.