De novo p62 condensation facilitates aggregate coarsening in a size-dependent manner.

Abstract

Listen

Translate article

The formation of mesoscale assemblies from individual proteins is an important process across various cellular functions. P62/SQSTM1 (p62) is an oligomeric protein suggested to assemble into liquid-like condensates which sequester misfolded, aberrant protein species including those found in neurodegenerative diseases. Many such proteins are aggregation-prone, forming increasingly large solid-like aggregates over the timescale of disease progression. Studies have addressed the capacity of p62 condensates to sequester diffuse ubiquitinated proteins, but the interplay between liquid-like p62 droplets and solid-like protein aggregates has remained unclear. Here, we demonstrate that de novo p62 condensation has the capacity to cluster aggregates, potentially enhancing aggregate coarsening. By using an engineered system to drive p62 condensation in aggregate-expressing cells, we observed robust interactions between de novo p62 condensates and pathological aggregates, leading to increased aggregate coarsening. Inducing p62 condensation alongside Huntington polyQ and tau aggregates revealed that disparities in sizes between the liquid-like condensates and solid-like substrates favor differing outcomes. P62 condensates have the capacity to cluster significantly smaller aggregates on their interface, while aggregate densification and growth increasingly promotes recruitment of p62 onto aggregates. This process reflects the importance of interfacial forces and energetics within cells, and suggests a mechanism for the sequestration and targeting of aggregation-prone species at condensate surfaces.