Polyphosphate modulates the stress-responsive formation of functional RNA-protein condensates in bacteria and mammalian cells

Uncovering what drives select biomolecules to form phase-separated condensates in vivo and identifying their physiological significance are topics of fundamental importance. Here, we show that nitrogen-starved Escherichia coli produces long-chain polyphosphates, which scaffold the RNA chaperone Hfq into high molecular weight complexes, which eventually phase separate together with components of the RNA translation and processing machinery. The presence of polyphosphate within these condensates controls Hfq function by selectively stabilizing polyadenylated RNAs involved in transcription and protein translation and by promoting interactions with translation- and RNA-metabolism-associated proteins involved in de novo protein synthesis. Lack of polyphosphate significantly impairs condensate formation, increases cell death, and hinders recovery from N-starvation. In functional analogy, we demonstrate that polyP contributes specifically to the formation of Processing (P)-bodies in human cell lines, revealing that a single, highly conserved and ancestral polyanion serves as a modulator for functional phase-separated condensate formation across the tree of life.