Involvement of miR-196a in HIV-associated neurocognitive disorders
Involvement of miR-196a in HIV-associated neurocognitive disorders
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DOI：
10.1007/s10495-014-1003-2
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发表时间：
2014-08-01
期刊：
影响因子：
7.2
通讯作者：
Sawaya, Bassel E.
中科院分区：
文献类型：
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作者：
Bagashev, Asen;Mukerjee, Ruma;Sawaya, Bassel E.
人类免疫缺陷病毒1型（HIV-1）转录反式激活因子（Tat）蛋白在神经元失调和HIV-1相关神经认知障碍（HAND）发展中的参与已经被充分探索；然而，其中的机制尚不清楚。为了寻找其机制，我们证明了Tat通过一个涉及p73和p53通路的通路来调节神经元功能。我们发现Tat使用microRNA-196a （miR-196a）来解除p73通路的调控。此外，我们发现Abelson小鼠白血病（c-Abl）磷酸化酪氨酸残基99 （Tyr-99）上的p73。有趣的是，在miR-196a模拟物存在下，Tat失去了促进p73积累和磷酸化的能力。有趣的是，通过细胞活力测定，p73的积累并未导致神经元细胞凋亡。使用针对视网膜母细胞瘤（Rb）蛋白丝氨酸残基807和811的抗体进行Western blot分析也用于验证我们关于细胞死亡缺失的数据。RB （S807/811）的过度磷酸化是细胞神经元活力的指示。这些结果强调了p73和microRNA在Tat处理的神经元中发挥的关键作用，导致它们的失调，并从机制上解释了Tat用于导致神经元功能障碍的途径之一，从而促进了HAND的发展。
Involvement of the human immunodeficiency virus type 1 (HIV-1) trans-activator of transcription (Tat) protein in neuronal deregulation and in the development of HIV-1 associated neurocognitive disorders (HAND) has been amply explored; however the mechanisms involved remain unclear. In search for the mechanisms, we demonstrated that Tat deregulates neuronal functions through a pathway that involved p73 and p53 pathway. We showed that Tat uses microRNA-196a (miR-196a) to deregulate the p73 pathway. Further, we found that the Abelson murine leukemia (c-Abl) phosphorylates p73 on tyrosine residue 99 (Tyr-99) in Tat-treated cells. Interestingly, Tat lost its ability to promote accumulation and phosphorylation of p73 in the presence of miR-196a mimic. Interestingly, accumulation of p73 did not lead to neuronal cell death by apoptosis as obtained by cell viability assay. Western blot analysis using antibodies directed against serine residues 807 and 811 of retinoblastoma (Rb) protein was also used to validate our data regarding lack of cell death. Hyperphosphorylation of RB (S807/811) is an indication of cell neuronal viability. These results highlight the key role played by p73 and microRNA in Tat-treated neurons leading to their deregulation and it deciphers mechanistically one of the pathways used by Tat to cause neuronal dysfunction that contributes to the development of HAND.