Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells.
Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells.
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Menin 介导 SIV 感染的猕猴大脑额叶皮层和 Tat 处理的细胞中 Tat 诱导的神经元凋亡
DOI：
10.18632/oncotarget.14993
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发表时间：
2017-03-14
期刊：
影响因子：
--
通讯作者：
Xing HQ
中科院分区：
文献类型：
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作者：
Wang J;Zhang Y;Xu Q;Qiu J;Zheng H;Ye X;Xue Y;Yin Y;Zhang Z;Liu Y;Hao Y;Wei Q;Wang W;Mori K;Izumo S;Kubota R;Shao Y;Xing HQ
人类免疫缺陷病毒（HIV）相关的神经认知障碍（HAND）的分子机制仍然知之甚少。最近有报道HIV-1达特反式激活需要menin，提示menin可能参与HAND的发病机制。但menin的作用尚不清楚。在这里，我们发现，与对照组相比，猴-人免疫缺陷嵌合病毒（SHIV）-SF162.P4和猴免疫缺陷病毒（SIV）sm 543 -3感染恒河猴menin蛋白水平增加免疫组化（IHC）和蛋白质印迹。Menin主要表达于大脑额叶皮质神经元，且menin染色细胞数与cleaved-caspase-3阳性细胞数呈正相关，与神经元特异性核蛋白NeuN阳性细胞数呈负相关，提示menin的表达可能诱导神经元凋亡。进一步的研究表明，在Tat诱导的细胞凋亡过程中，menin水平显著增加，而通过p113.7-MEN 1-shRNA下调menin减弱了Tat诱导的SY 5 Y细胞和原代神经元培养物中caspase-3和caspase-8的切割。总之，我们的研究结果揭示了menin在SIV感染的猕猴和培养的神经元的脑中的促凋亡作用，表明靶向menin可能有潜力阻断HAND中HIV-1达特诱导的神经元损伤。
The molecular mechanisms involved in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remain poorly understood. It has been recently reported that HIV-1 Tat transactivation requires menin, suggesting that menin may be involved in HAND pathogenesis. But the role of menin is not clear. Here, we found that protein level of menin was increased in simian-human immunodeficiency chimeric virus (SHIV)-SF162.P4 and simian immunodeficiency virus (SIV) sm543-3-infected rhesus macaques compared with the controls by immunohistochemistry (IHC) and western blot. Menin mainly expressed in the frontal cortex neurons of the brain, more importantly, the number of menin-staining cells was positively correlated with cleaved-caspase-3-positive cells while it was negatively correlated with a neuron-specific nuclear protein NeuN-positive cells, suggesting that expression of menin may induce neuronal apoptosis. Further studies showed that menin level was significantly increased during Tat-induced apoptosis, while downregulation of menin by pll3.7-MEN1-shRNA attenuated the Tat-induced cleavage of caspase-3 and caspase-8 in SY5Y cells and primary neuron cultures. Together, our findings reveal a pro-apoptotic role of menin in the brains of the SIV-infected macaques and the cultured neurons, indicating that targeting menin may be potential to block the HIV-1 Tat induced neuronal damage in HAND.