Down-regulation of NAMPT expression by miR-182 is involved in Tat-induced HIV-1 long terminal repeat (LTR) transactivation
Down-regulation of NAMPT expression by miR-182 is involved in Tat-induced HIV-1 long terminal repeat (LTR) transactivation
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DOI：
10.1016/j.biocel.2012.11.002
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发表时间：
2013-02-01
影响因子：
4
通讯作者：
Ruan, Zheng
中科院分区：
文献类型：
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作者：
Chen, Xin-Yu;Zhang, Hong-Sheng;Ruan, Zheng
Tat 的反式激活活性由沉默调节蛋白 1 (SIRT1) 控制，该蛋白将 HIV 转录与细胞的代谢状态联系起来。烟酰胺磷酸核糖转移酶 (NAMPT) 是参与能量代谢的烟酰胺腺嘌呤二核苷酸 (NAD(+)) 合成挽救途径中的关键酶。宿主编码的 microRNA (miRNA) 可能会影响病毒复制。在本研究中，我们的目标是研究TZM-bl细胞中miR-182的调节，并探讨miR-182通过下调NAMPT表达影响Tat诱导的HIV-1反式激活的机制。我们发现，当 Tat 在 T2M-bl 细胞中表达时，miR-182 上调。 MiR-182 通过作用于 NAMPT mRNA 的 3'-UTR 显着抑制 NAMPT 蛋白表达。 MiR-182 参与 Tat 诱导的 NAD(+) 消耗、SIRT1 蛋白表达和活性下调、p65 乙酰化增加。 “miR-182 模拟物”的强制表达增加了 Tat 诱导的 LTR 反式激活。我们的结果揭示了 Tat 和靶向 NAMPT 的特定宿主细胞 miRNA 之间以前未知的联系。我们的结果表明，通过下调 miR-182 来增强 NAMPT 蛋白表达的策略可能具有预防 HIV-1 复制的治疗益处。 (C) 2012 Elsevier Ltd. 保留所有权利。
Tat's transactivating activity is controlled by sirtuin 1 (SIRT1) that connects HIV transcription with the metabolic state of the cell. Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in the salvaging pathway for the synthesis of nicotinamide adenine dinucleotide (NAD(+)) that is involved in energy metabolism. Host encoded microRNAs (miRNAs) may influence viral replication. In this study, our goal was aimed to investigate the regulation of miR-182 in TZM-bl cells and explore the mechanisms by which miR-182 influenced Tat-induced HIV-1 transactivation through targeting at down-regulation of NAMPT expression. We showed that miR-182 was up-regulated when Tat was expressed in T2M-bl cells. MiR-182 significantly inhibited NAMPT protein expression by acting on the 3'-UTR of the NAMPT mRNA. MiR-182 was involved in Tat-induced NAD(+) depletion, down-regulation of SIRT1 protein expression and activity, increased acetylation of p65. Forced expression of "miR-182 mimics" increased Tat-induced LTR transactivation. Our results uncover previously unknown links between Tat and a specific host cell miRNA that targets NAMPT. Our results suggest that strategies to augment NAMPT protein expression by down-regulation of miR-182 may have therapeutic benefits to prevent HIV-1 replication. (C) 2012 Elsevier Ltd. All rights reserved.