From condensates to fibrils: polyphosphate-regulated phase separation of p53

Protein aggregation is widely associated with neurodegenerative disorders, but increasing evidence suggests that similar misfolding phenomena also contribute to cancer. Although p53 aggregation is commonly associated with oncogenic mutations, wild-type p53 can also misfold under cellular stress. Here, we show that the endogenous polyanion polyphosphate regulates the phase behaviour and aggregation of wild-type p53 in a pH-dependent manner. Using thioflavin T kinetics together with optical and electron microscopy, we demonstrate that acidic conditions promote polyphosphate-driven coacervation of p53, leading to the formation of multicoacervate condensates. These protein-rich condensates locally concentrate p53 and accelerate fibril nucleation and maturation into dense fibrillar networks. In contrast, at neutral pH, p53 remains soluble and non-amyloidogenic, consistent with the absence of phase separation. Together, our findings reveal a phase separation-assisted pathway for p53 fibrillization under acidic stress and highlight polyphosphate as an important regulator of p53 aggregation.