Eukaryotic cell biology is temporally coordinated to support the energetic demands of protein homeostasis

John S. O’Neill, Nathaniel P. Hoyle, J. Brian Robertson, Rachel S. Edgar, Andrew D. Beale, Sew Y. Peak-Chew, Jason Day, Ana S. H. Costa, Christian Frezza, Helen C. Causton

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Received Date: 5th May 20

Under continuous nutrient-limited conditions every aspect of yeast physiology is subject to robust temporal regulation1-6, resulting in biological oscillations whose function and mechanism is poorly resolved7. Here we show that these cellular rhythms occur to minimise energy expenditure by temporally restricting protein synthesis until sufficient cellular resources are present, whilst maintaining osmotic homeostasis and protein quality control. Although nutrient supply is constant, cells initially ‘sequester and store’ metabolic resources: accumulating polysaccharides, amino acids, K+ and other osmolytes via increased transport, autophagy and biomolecular condensation, maintained by low cytosolic pH. Replete stores trigger increased H+ export to elevate cytosolic pH, thereby stimulating TORC1 and liberating proteasomes, ribosomes, chaperones and metabolic enzymes from non-membrane bound compartments. This facilitates bursts of increased protein synthesis, the liquidation of storage carbohydrates to sustain higher respiration rates and increased ATP turnover, and export of osmolytes to maintain osmotic potential. Since the duration of translational bursting is determined by cell-intrinsic factors, the period of oscillation is determined by the time cells take to store sufficient resources to license passage through the pH-dependent metabolic checkpoint that initiates translational bursting. We propose that dynamic regulation of ion transport and metabolic plasticity are required to maintain osmotic and protein homeostasis during remodelling of eukaryotic proteomes, and that bioenergetic constraints have favoured temporal organisation that promotes oscillations.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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