期刊
NATURE
卷 578, 期 7794, 页码 296-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-1982-9
关键词
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资金
- AMED [JP18gm1110003, JP19gm1110010]
- MEXT/JSPS KAKENHI [JP18K19352, JP18K14913, JP26293018, JP18H03993, JP18H05498, JP18H03977, JP 19H05281, JP21000012]
- Takeda Science Foundation
- Uehara Memorial Foundation
- European Commission [FP7 GA ERC-2012-SyG_318987-ToPAG]
- DFG [EXC 2067/1- 390729940]
The proteasome is a major proteolytic machine that regulates cellular proteostasis through selective degradation of ubiquitylated proteins(1,2). 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 autophagosomes(3-8), 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. Hyperosmotic stress leads to a phase separation of the proteasome, triggered by interactions between RAD23B and ubiquitylated proteins, which bring together p97 and proteasome-associated proteins into nuclear proteolytic foci.
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