Zhang Tao, Baldie Gerard, Periz Goran, Wang Jiou
1 Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland, United States of America, 2 Department of Neuroscience, School of Medicine, The Johns Hopkins University, Baltimore, Maryland, United States of America.
PLoS Genet. 2014 Oct 16;10(10):e1004693. doi: 10.1371/journal.pgen.1004693. eCollection 2014 Oct.
Protein homeostasis is critical for cell survival and functions during stress and is regulated at both RNA and protein levels. However, how the cell integrates RNA-processing programs with post-translational protein quality control systems is unknown. Transactive response DNA-binding protein (TARDBP/TDP-43) is an RNA-processing protein that is involved in the pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we report a conserved role for TDP-43, from C. elegans to mammals, in the regulation of protein clearance via activation of FOXO transcription factors. In response to proteotoxic insults, TDP-43 redistributes from the nucleus to the cytoplasm, promoting nuclear translocation of FOXOs and relieving an inhibition of FOXO activity in the nucleus. The interaction between TDP-43 and the FOXO pathway in mammalian cells is mediated by their competitive binding to 14-3-3 proteins. Consistent with FOXO-dependent protein quality control, TDP-43 regulates the levels of misfolded proteins. Therefore, TDP-43 mediates stress responses and couples the regulation of RNA metabolism and protein quality control in a FOXO-dependent manner. The results suggest that compromising the function of TDP-43 in regulating protein homeostasis may contribute to the pathogenesis of related neurodegenerative diseases.
蛋白质稳态在应激期间对细胞存活和功能至关重要，并且在RNA和蛋白质水平上均受到调控。然而，细胞如何将RNA加工程序与翻译后蛋白质质量控制系统整合尚不清楚。反式激活反应DNA结合蛋白（TARDBP/TDP-43）是一种RNA加工蛋白，参与包括肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）在内的主要神经退行性疾病的发病机制。在此，我们报道了从秀丽隐杆线虫到哺乳动物，TDP-43在通过激活FOXO转录因子调节蛋白质清除方面的保守作用。响应蛋白毒性损伤时，TDP-43从细胞核重新分布到细胞质，促进FOXO的核转位并解除对细胞核中FOXO活性的抑制。哺乳动物细胞中TDP-43与FOXO途径之间的相互作用由它们与14-3-3蛋白的竞争性结合介导。与FOXO依赖性蛋白质质量控制一致，TDP-43调节错误折叠蛋白的水平。因此，TDP-43介导应激反应，并以FOXO依赖性方式将RNA代谢调节与蛋白质质量控制联系起来。结果表明，损害TDP-43在调节蛋白质稳态中的功能可能导致相关神经退行性疾病的发病机制。
