Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate.

Abstract

Covalent attachment of polyubiquitin chains to eukaryotic proteins is a common protein quality control signal. Ubiquitination often marks proteins for degradation by the proteasome, but can also drive non-degradative outcomes. Proteins, including UBQLN2, that bind both polyubiquitin and the proteasome can either enhance or inhibit degradation. The ALS-related UBQLN2 is recruited to membraneless organelles, including stress granules, and undergoes phase separation in vitro , but the effects of phase separation on substrate fate are unknown. Herein we show that UBQLN2 phase separation is modulated by polyubiquitinated substrates in a linkage-dependent fashion. We show that two functional outcomes, degradation and deubiquitination, are differentially affected by phase separation. Our results suggest that phase separation of substrates and UBQLN2 could control protein fates.