Role of Proteostasis Regulation in the Turnover of Stress Granules.
Role of Proteostasis Regulation in the Turnover of Stress Granules.
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DOI：
10.3390/ijms232314565
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发表时间：
2022-11-23
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
RNA结合蛋白（RBP）和RNA可以形成动态的液滴样细胞质凝聚物，称为应激颗粒（SG），以响应各种细胞应激。这一过程由RBP和RNA之间的多价相互作用介导的液-液相分离驱动。SG的形成允许某些细胞活动的暂时暂停，例如不必要的蛋白质的翻译。同时，非翻译mRNA也可能被隔离和停滞。在应力消除后，SG被分解以恢复暂停的生物过程并恢复正常的细胞功能。SG相关RBP中的长期应激和致病突变可导致异常SG的形成和/或损害SG分解，从而增加病理性蛋白质聚集的风险。维持蛋白质稳态（proteostasis）的机制包括分子伴侣和辅伴侣、泛素-蛋白酶体系统、自噬和其他成分，并参与SG代谢的调节。最近，蛋白质稳态已被确定为SG营业额的主要调节器。在这里，我们总结了新的研究结果的特定功能的蛋白酶抑制机制在调节SG拆卸和清除，讨论SG营业额在神经退行性疾病的病理和临床意义，并指出未解决的问题，值得今后的探索。
RNA-binding proteins (RBPs) and RNAs can form dynamic, liquid droplet-like cytoplasmic condensates, known as stress granules (SGs), in response to a variety of cellular stresses. This process is driven by liquid–liquid phase separation, mediated by multivalent interactions between RBPs and RNAs. The formation of SGs allows a temporary suspension of certain cellular activities such as translation of unnecessary proteins. Meanwhile, non-translating mRNAs may also be sequestered and stalled. Upon stress removal, SGs are disassembled to resume the suspended biological processes and restore the normal cell functions. Prolonged stress and disease-causal mutations in SG-associated RBPs can cause the formation of aberrant SGs and/or impair SG disassembly, consequently raising the risk of pathological protein aggregation. The machinery maintaining protein homeostasis (proteostasis) includes molecular chaperones and co-chaperones, the ubiquitin-proteasome system, autophagy, and other components, and participates in the regulation of SG metabolism. Recently, proteostasis has been identified as a major regulator of SG turnover. Here, we summarize new findings on the specific functions of the proteostasis machinery in regulating SG disassembly and clearance, discuss the pathological and clinical implications of SG turnover in neurodegenerative disorders, and point to the unresolved issues that warrant future exploration.
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