Stress- and ubiquitylation-dependent phase separation of the proteasome

Sayaka Yasuda, Hikaru Tsuchiya, Ai Kaiho, Qiang Guo, Ken Ikeuchi, Akinori Endo, Naoko Arai, Fumiaki Ohtake, Shigeo Murata, Toshifumi Inada, Wolfgang Baumeister, Rubén Fernández-Busnadiego, Keiji Tanaka, Yasushi Saeki

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The proteasome is a major proteolytic machine that regulates cellular proteostasis through selective degradation of ubiquitylated proteins1,2. A number of ubiquitin-related molecules have recently been found to be involved in the regulation of biomolecular condensates or membraneless organelles, which arise by liquid–liquid phase separation of specific biomolecules, including stress granules, nuclear speckles and autophagosomes3–8, but it remains unclear whether the proteasome also participates in such regulation. Here we reveal that proteasome-containing nuclear foci form under acute hyperosmotic stress. These foci are transient structures that contain ubiquitylated proteins, p97 (also known as valosin-containing protein (VCP)) and multiple proteasome-interacting proteins, which collectively constitute a proteolytic centre. The major substrates for degradation by these foci were ribosomal proteins that failed to properly assemble. Notably, the proteasome foci exhibited properties of liquid droplets. RAD23B, a substrate-shuttling factor for the proteasome, and ubiquitylated proteins were necessary for formation of proteasome foci. In mechanistic terms, a liquid–liquid phase separation was triggered by multivalent interactions of two ubiquitin-associated domains of RAD23B and ubiquitin chains consisting of four or more ubiquitin molecules. Collectively, our results suggest that ubiquitin-chain-dependent phase separation induces the formation of a nuclear proteolytic compartment that promotes proteasomal degradation.

Original languageEnglish
Pages (from-to)296-300
Number of pages5
JournalNature
Volume578
Issue number7794
DOIs
Publication statusPublished - 2020 Feb 13

ASJC Scopus subject areas

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    Yasuda, S., Tsuchiya, H., Kaiho, A., Guo, Q., Ikeuchi, K., Endo, A., Arai, N., Ohtake, F., Murata, S., Inada, T., Baumeister, W., Fernández-Busnadiego, R., Tanaka, K., & Saeki, Y. (2020). Stress- and ubiquitylation-dependent phase separation of the proteasome. Nature, 578(7794), 296-300. https://doi.org/10.1038/s41586-020-1982-9