Kasu Yasar Arfat T, Arva Akshaya, Johnson Jess, Sajan Christin, Manzano Jasmin, Hennes Andrew, Haynes Jacy, Brower Christopher S
Department of Biology, Texas Woman's University, P.O. Box 425799, Denton, TX 76204, USA.
iScience. 2022 Apr 20;25(5):104273. doi: 10.1016/j.isci.2022.104273. eCollection 2022 May 20.
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.
神经退行性变与因错误折叠和/或蛋白水解切割而带有溶剂暴露疏水性的蛋白质聚集有关。了解防止蛋白质聚集的细胞蛋白质质量控制机制对于理解神经退行性变的病因至关重要。通过研究与疾病相关的TAR DNA结合蛋白43（TDP43）的C末端片段的代谢，我们发现Bcl-2相关抗凋亡蛋白6（BAG6）作为带有暴露疏水性的蛋白水解片段的传感器，可防止其在细胞内聚集。此外，BAG6通过招募泛素连接酶环指蛋白126（RNF126）促进TDP43片段的泛素化。为证实其在防止聚集方面的作用，我们发现在没有BAG6的情况下，TDP43片段会形成细胞内聚集体。最后，我们发现BAG6可以与其他神经退行性变相关的蛋白水解片段相互作用并使其溶解。因此，BAG6在预防与神经退行性变相关的细胞内聚集方面发挥着普遍作用。
