Volume buffering in multi-component phase separation

The concentrations of biomolecules in cells are subject to substantial fluctuations, but how cells deal with such variability is still poorly understood. Recently the formation of biomolecular condensates through liquid-liquid phase separation has been proposed as a powerful buffering mechanism to enable local protein concentration to be robust to expression fluctuations. Here, using theory, simulations, in vitro and in vivo experiments we show an orthogonal noise buffering mechanism mediated by phase separation, whereby the total volume of condensates is buffered when the global protein concentration changes. Spatial control mechanisms are needed to robustly localize cellular activities and volume buffering by phase separation offers such a mechanism. Our work thus provides new insights into the potential role of condensates in regulating spatial activities in cells.