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蛋白酶体可发生压力和泛素化依赖的相分离
2020-02-12 13:11

日本东京大学医科学研究所Yasushi Saeki 和Keiji Tanaka合作发现蛋白酶体可发生压力和泛素化依赖的相分离。这一研究成果在线发表在2020年2月5日的国际学术期刊《自然》上。

研究人员发现在急性高渗应激下可形成含有蛋白酶体的核斑点。这些斑点是瞬时结构,其中包含泛素化蛋白,p97(也称为含缬酪肽的蛋白(VCP))和多种与蛋白酶体相互作用的蛋白,它们共同构成了蛋白水解中心。这些位点降解的底物主要是无法正确组装核糖体蛋白。值得注意的是,这些蛋白酶体斑点具有液滴的特性。RAD23B是蛋白酶体的底物转运因子,而泛素化的蛋白质对于形成此蛋白酶体斑点是必需的。从机理上讲,RAD23B的两个泛素相关结构域和由四个或更多泛素分子组成的泛素链相互作用引起液-液相分离。总的来说,该研究结果表明,泛素链依赖的相分离促进蛋白酶体降解核蛋白水解区室的形成。

据介绍,蛋白酶体是主要的蛋白水解机器,它通过选择性降解泛素化蛋白来调节细胞蛋白水解。最近研究发现许多泛素相关分子参与生物分子缩合物或无膜细胞器的调控,这些分子是由特定生物分子发生液-液相分离产生的,包括应力颗粒、核斑点和自噬体。但仍不清楚蛋白酶体是否也通过液-液相分离发挥调控功能。

附:英文原文

Title: Stress- and ubiquitylation-dependent phase separation of the proteasome

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

Issue&Volume: 2020-02-05

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 autophagosomes3,4,5,6,7,8, 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.

DOI: 10.1038/s41586-020-1982-9

Source: https://www.nature.com/articles/s41586-020-1982-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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