Interaction of amyotrophic lateral sclerosis/frontotemporal lobar degeneration-associated fused-in-sarcoma with proteins involved in metabolic and protein degradation pathways
Interaction of amyotrophic lateral sclerosis/frontotemporal lobar degeneration-associated fused-in-sarcoma with proteins involved in metabolic and protein degradation pathways
复制标题
肌萎缩侧索硬化症/额颞叶变性相关融合肉瘤与参与代谢和蛋白质降解途径的蛋白质的相互作用
DOI：
10.1016/j.neurobiolaging.2014.07.044
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发表时间：
2015-01-01
影响因子：
4.2
通讯作者：
Xu, Jin
中科院分区：
文献类型：
--
作者：
Wang, Tao;Jiang, Xin;Xu, Jin
融合肉瘤（FUS）是一种与肌萎缩侧索硬化和额颞叶痴呆相关的核蛋白。在病理条件下，FUS经常积累在胞质中，但这种改变的分布如何影响FUS的蛋白质相互作用模式尚不清楚。使用双标签亲和纯化和质谱分析，我们比较了野生型FUS和P525 L突变体的相互作用组，该突变体导致青少年肌萎缩侧索硬化症的最严重表型。突变体FUS保留了结合参与RNA代谢的蛋白质的能力。我们发现P525 L与许多代谢酶的结合显著增加。此外，我们还鉴定并证实了FUS与一些参与神经退行性疾病和/或泛素蛋白酶体途径的蛋白质之间的新相互作用，如VCP/p97、PSF、乌巴1和26 S蛋白酶体非ATP酶调节亚基12（PSMD 12/Rpn 5）。因此，我们观察到随着FUS积累，细胞中ATP水平显着降低，多聚遍在蛋白质的积累增加。因此，我们的研究提出了新的机制，即FUS积累导致有缺陷的能量代谢和蛋白质降解，直接与这些途径中的关键调控因子相互作用。(C)2015 Elsevier Inc. All rights reserved.
Fused-in-sarcoma (FUS) is a nuclear protein linked to amyotrophic lateral sclerosis and frontotemporal dementia. Under pathologic conditions, FUS frequently is accumulated in cytosoplasm, but how this altered distribution affects the protein interaction pattern of FUS is unclear. Using dual-tag affinity purification and mass spectrometry, we compared the interactome of the wild-type FUS and the P525 L mutant, which causes juvenile amyotrophic lateral sclerosis with the most severe phenotypes. The mutant FUS retained the ability to bind proteins involved in RNA metabolism. We found significant increased binding of P525 L to many metabolic enzymes. Furthermore, we identified and confirmed some novel interactions between FUS and proteins involved in neurodegenerative diseases and/or ubiquitin proteasome pathway, such as VCP/p97, PSF, UBA 1, and 26S proteosome non-ATPase regulatory subunit 12 (PSMD12/Rpn5). Accordingly, we have observed significantly reduced ATP levels and increased accumulation of poly-ubiquitinated proteins in cells with FUS accumulation. Therefore, our study suggested new mechanisms whereby FUS accumulation leads to defective energy metabolism and protein degradation by directly interacting with key regulators in these pathways. (C) 2015 Elsevier Inc. All rights reserved.