Parkinson's disease (PD) is characterized by the progressive loss of midbrain dopamine neurons in the substantia nigra. Mutations in the F-box only protein 7 gene (Fbxo7) have been reported to cause an autosomal recessive form of early-onset familial PD. FBXO7 is a part of the SKP1-Cullin1-F-box (SCF) E3 ubiquitin ligase complex, which mediates ubiquitination of numerous substrates. FBXO7 also regulates mitophagy, cell growth, and proteasome activity. A member of the FOXO family, the transcription factor FOXO4, is also known to modulate several cellular responses, including cell cycle progression and apoptosis; however, the relationship between FBXO7 and FOXO4 has not been investigated. In this study, we determined that FBXO7 binds to FOXO4 and negatively regulates intracellular FOXO4 levels. Interestingly, we also found that FBXO7-mediated degradation of FOXO4 did not occur through either of two major proteolysis systems, the ubiquitin-proteasome system or the lysosome-autophagy pathway, although it was blocked by a caspase 8-specific inhibitor and caspase 8-knockdown. Moreover, intracellular FOXO4 levels were greatly reduced in dopaminergic MN9D cells following treatment with neurotoxic 6-hydroxydopamine (6-OHDA), which was produced upon FBXO7-mediated and caspase 8-mediated proteolysis. Taken together, these results suggest that FOXO4 is negatively regulated in FBXO7-linked PD through caspase 8 activation, suppressing the cytoprotective effect of FOXO4 during 6-OHDA-induced neuronal cell death.

中文翻译：

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FBXO7 触发 caspase 8 介导的转录因子 FOXO4 蛋白水解，并加剧神经元细胞毒性。

帕金森病（PD）的特征是黑质中脑多巴胺神经元的逐渐丧失。据报道，仅 F-box 蛋白 7 基因 (Fbxo7) 的突变可导致常染色体隐性遗传的早发家族性 PD。FBXO7 是 SKP1-Cullin1-F-box (SCF) E3 泛素连接酶复合物的一部分，可介导多种底物的泛素化。FBXO7 还调节线粒体自噬、细胞生长和蛋白酶体活性。FOXO 家族的成员转录因子 FOXO4 也可调节多种细胞反应，包括细胞周期进程和细胞凋亡；然而，FBXO7 和 FOXO4 之间的关系尚未得到研究。在这项研究中，我们确定 FBXO7 与 FOXO4 结合并负向调节细胞内 FOXO4 水平。有趣的是，我们还发现 FBXO7 介导的 FOXO4 降解并不通过两个主要的蛋白水解系统（泛素蛋白酶体系统或溶酶体自噬途径）发生，尽管它被 caspase 8 特异性抑制剂和 caspase 8- 阻断。击倒。此外，多巴胺能 MN9D 细胞经神经毒性 6-羟基多巴胺 (6-OHDA) 处理后，细胞内 FOXO4 水平大大降低，6-OHDA 是由 FBXO7 介导和 caspase 8 介导的蛋白水解产生的。综上所述，这些结果表明 FOXO4 在 FBXO7 相关的 PD 中通过 caspase 8 激活受到负向调节，从而抑制 FOXO4 在 6-OHDA 诱导的神经元细胞死亡过程中的细胞保护作用。