a Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Pathology , Basic Medicine, Medical College, Xiamen University , Xiamen , China.
b Institute of Laboratory Animal Sciences of Chinese Academy of Medical Science , Beijing , China.
Cell Cycle. 2018;17(13):1614-1623. doi: 10.1080/15384101.2018.1480219. Epub 2018 Aug 21.
The human immunodeficiency virus-1 (HIV-1) regulatory protein Tat plays an important role during HIV-1-associated neurocognitive disorders (HAND) by inducing neuronal autophagy. In this study, we used immunohistochemistry, immunofluorescence, western blot, qRT-PCR, and RNA interference to elucidate the involvement of Bcl-2-associated athanogene 3 (BAG3) in the pathogenesis of HIV-1 Tat-induced autophagy during HAND. We found that BAG3 expression is elevated in astrocytes in frontal cortex of macaques infected with simian immunodeficiency virus-human immunodeficiency chimeric virus (SHIV). In addition, in human primary glioblastoma cells (U87), HIV-1 Tat upregulated BAG3 in an NF-κB-dependent manner to induce autophagy. Importantly, suppression of BAG3 or inhibition of NF-κB activity reversed the HIV-1 Tat-induced autophagy. These results indicate that HIV-1 Tat induces autophagy by upregulating BAG3 via NF-κB signaling, which suggests BAG3 and NF-κB could potentially serve as novel targets for HAND therapies.
人类免疫缺陷病毒 1（HIV-1）调节蛋白 Tat 通过诱导神经元自噬在 HIV-1 相关神经认知障碍（HAND）中发挥重要作用。在这项研究中，我们使用免疫组织化学、免疫荧光、Western blot、qRT-PCR 和 RNA 干扰来阐明 Bcl-2 相关抗凋亡基因 3（BAG3）在 HAND 中 HIV-1 Tat 诱导自噬发病机制中的作用。我们发现感染猴免疫缺陷病毒-人免疫缺陷嵌合病毒（SHIV）的猕猴额皮质星形胶质细胞中 BAG3 表达升高。此外，在人原发性神经胶质瘤细胞（U87）中，HIV-1 Tat 通过 NF-κB 依赖性方式上调 BAG3 以诱导自噬。重要的是，抑制 BAG3 或抑制 NF-κB 活性可逆转 HIV-1 Tat 诱导的自噬。这些结果表明，HIV-1 Tat 通过 NF-κB 信号转导上调 BAG3 诱导自噬，这表明 BAG3 和 NF-κB 可能成为 HAND 治疗的新靶点。
