BAG6 prevents the aggregation of neurodegeneration-associated fragments of TDP43.
BAG6 prevents the aggregation of neurodegeneration-associated fragments of TDP43.
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DOI：
10.1016/j.isci.2022.104273
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发表时间：
2022-05-20
期刊：
影响因子：
5.8
通讯作者：
Brower, Christopher S.
中科院分区：
文献类型：
--
作者：
Kasu, Yasar Arfat T.;Arva, Akshaya;Johnson, Jess;Sajan, Christin;Manzano, Jasmin;Hennes, Andrew;Haynes, Jacy;Brower, Christopher S.
神经变性与由于其错误折叠和/或蛋白水解裂解而具有溶剂暴露的疏水性的蛋白质的聚集有关。了解防止蛋白质聚集的细胞蛋白质质量控制机制是了解神经变性病因学的基础。通过检查疾病相关的TAR DNA结合蛋白43（TDP 43）的C-末端片段的代谢，我们发现Bcl-2相关的产气基因6（BAG 6）作为具有暴露的疏水性的蛋白水解片段的传感器发挥作用，并防止它们的细胞内聚集。此外，BAG 6通过募集Ub-连接酶，环指蛋白126（RNF 126）促进TDP 43片段的泛素化。验证其在防止聚集中的作用，我们发现TDP 43片段在BAG 6不存在的情况下形成细胞内聚集体。最后，我们发现BAG 6可以与其他神经变性相关的蛋白水解片段相互作用并溶解。因此，BAG 6在防止与神经变性相关的细胞内聚集中起一般作用。蛋白水解切割产生具有暴露的疏水性的蛋白质片段BAG 6维持溶解性并指导蛋白质片段的降解BAG 6防止与神经变性相关的细胞内聚集生物科学;分子生物学;神经科学;分子神经科学;细胞生物学
Neurodegeneration is associated with the aggregation of proteins bearing solvent-exposed hydrophobicity as a result of their misfolding and/or proteolytic cleavage. An understanding of the cellular protein quality control mechanisms which prevent protein aggregation is fundamental to understanding the etiology of neurodegeneration. By examining the metabolism of disease-linked C-terminal fragments of the TAR DNA-binding protein 43 (TDP43), we found that the Bcl-2 associated athanogene 6 (BAG6) functions as a sensor of proteolytic fragments bearing exposed hydrophobicity and prevents their intracellular aggregation. In addition, BAG6 facilitates the ubiquitylation of TDP43 fragments by recruiting the Ub-ligase, Ring finger protein 126 (RNF126). Authenticating its role in preventing aggregation, we found that TDP43 fragments form intracellular aggregates in the absence of BAG6. Finally, we found that BAG6 could interact with and solubilize additional neurodegeneration-associated proteolytic fragments. Therefore, BAG6 plays a general role in preventing intracellular aggregation associated with neurodegeneration. Proteolytic cleavage generates protein fragments bearing exposed hydrophobicity BAG6 maintains the solubility and directs the degradation of protein fragments BAG6 prevents intracellular aggregation associated with neurodegeneration Biological sciences; Molecular biology; Neuroscience; Molecular neuroscience; Cell biology
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DOI：
10.1016/j.jbc.2021.100489
发表时间：
2021-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Checler F;Afram E;Pardossi-Piquard R;Lauritzen I
通讯作者：
Lauritzen I
影响因子：
3.6
作者：
Kubota S;Doi H;Koyano S;Tanaka K;Komiya H;Katsumoto A;Ikeda S;Hashiguchi S;Nakamura H;Fukai R;Takahashi K;Kunii M;Tada M;Takeuchi H;Tanaka F
通讯作者：
Tanaka F
影响因子：
16.6
作者：
Cohen, Todd J.;Hwang, Andrew W.;Restrepo, Clark R.;Yuan, Chao-Xing;Trojanowski, John Q.;Lee, Virginia M. Y.
通讯作者：
Lee, Virginia M. Y.
影响因子：
4.8
作者：
Budini, Mauricio;Buratti, Emanuele;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.
影响因子：
21.3
作者：
Connell, P;Ballinger, CA;Patterson, C
通讯作者：
Patterson, C