Condensate interfaces can accelerate protein aggregation

Chang-Hyun Choi; Daniel S W Lee; David W Sanders; Clifford P Brangwynne

doi:10.1016/j.bpj.2023.10.009

Condensate interfaces can accelerate protein aggregation

Biophys J. 2023 Oct 13:S0006-3495(23)00645-8. doi: 10.1016/j.bpj.2023.10.009. Online ahead of print.

Authors

Chang-Hyun Choi¹, Daniel S W Lee¹, David W Sanders¹, Clifford P Brangwynne²

Affiliations

¹ Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey.
² Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey; Omenn-Darling Bioengineering Institute, Princeton University, Princeton, New Jersey; Howard Hughes Medical Institute, Chevy Chase, Maryland. Electronic address: cbrangwy@princeton.edu.

PMID: 37837191
DOI: 10.1016/j.bpj.2023.10.009

Abstract

Protein aggregates, formed from the assembly of aberrant, misfolded proteins, are a hallmark of neurodegenerative diseases. Disease-associated aggregates such as mutant Huntingtin polyQ inclusions, are typically enriched in p62/SQSTM1, an oligomeric protein that binds to and sequesters aberrant proteins. p62 has been suggested to sequester proteins through formation of liquid-like biomolecular condensates, but the physical mechanisms by which p62 condensates may regulate pathological protein aggregation remain unclear. Here, we use a light-inducible biomimetic condensate system to show that p62 condensates enhance coarsening of mutant polyQ aggregates through interface-mediated sequestration, which accelerates polyQ accumulation into larger aggregates. However, the resulting large aggregates accumulate polyubiquitinated proteins, which depletes free p62, ultimately suppressing further p62 condensation. This dynamic interplay between interface-mediated coarsening of solid aggregates and downstream consequences on the phase behavior of associated regulatory proteins could contribute to the onset and progression of protein aggregation diseases.