Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation
Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation
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DOI：
10.3390/ph13060128
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发表时间：
2020-06
期刊：
影响因子：
4.6
通讯作者：
Hikaru Tsuchiya;Akinori Endo;Y. Saeki
中科院分区：
文献类型：
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作者：
Hikaru Tsuchiya;Akinori Endo;Y. Saeki
26 S蛋白酶体是一种2.5-MDa蛋白酶复合物，负责真核细胞中泛素化蛋白的选择性和ATP依赖性降解。蛋白酶体介导的蛋白质降解占基础条件下所有细胞蛋白质水解的约70%，因此任何功能障碍都可能导致细胞稳态的急剧变化。泛素化的主要功能是靶向蛋白质进行蛋白酶体降解。伴随着破译的结构多样性的泛素链与八个链接和链长，泛素代码的蛋白酶体降解已扩大超出最佳表征的赖氨酸48连接的泛素链。尽管多聚泛素化蛋白可以被蛋白酶体直接识别，但在某些情况下，这些蛋白需要被与多种细胞活性相关的保守ATP酶（AAA）-家族ATP酶p97/含缬草酸蛋白（VCP）复合物提取或分离，并由泛素样（UBL）-泛素相关（乌巴）蛋白护送到蛋白酶体;这些蛋白被称为底物穿梭因子。此外，蛋白酶体是高度移动的，并且响应于不同的细胞环境和应激而适当地时空调节。在这篇综述中，我们强调了p97，穿梭因子和蛋白酶体之间的一个新兴的关键环节，有效的蛋白酶体降解。我们还提出证据表明，蛋白酶体含有核灶形成的液-液相分离下急性高渗应激。
The 26S proteasome is a 2.5-MDa protease complex responsible for the selective and ATP-dependent degradation of ubiquitylated proteins in eukaryotic cells. Proteasome-mediated protein degradation accounts for ~70% of all cellular proteolysis under basal conditions, and thereby any dysfunction can lead to drastic changes in cell homeostasis. A major function of ubiquitylation is to target proteins for proteasomal degradation. Accompanied by deciphering the structural diversity of ubiquitin chains with eight linkages and chain lengths, the ubiquitin code for proteasomal degradation has been expanding beyond the best-characterized Lys48-linked ubiquitin chains. Whereas polyubiquitylated proteins can be directly recognized by the proteasome, in several cases, these proteins need to be extracted or segregated by the conserved ATPases associated with diverse cellular activities (AAA)-family ATPase p97/valosin-containing protein (VCP) complex and escorted to the proteasome by ubiquitin-like (UBL)–ubiquitin associated (UBA) proteins; these are called substrate-shuttling factors. Furthermore, proteasomes are highly mobile and are appropriately spatiotemporally regulated in response to different cellular environments and stresses. In this review, we highlight an emerging key link between p97, shuttling factors, and proteasome for efficient proteasomal degradation. We also present evidence that proteasome-containing nuclear foci form by liquid–liquid phase separation under acute hyperosmotic stress.