title: MiR-217 is involved in Tat-induced HIV-1 long terminal repeat (LTR) transactivation by down-regulation of SIRT1.
abstract: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and may contribute to the development and progression of many infective diseases including human immunodeficiency virus 1 (HIV-1) infection. The Tat protein is fundamental to viral gene expression. In this study, our goal was to investigate the regulation of a specific miRNA (known as miR-217) in multinuclear activation of galactosidase indicator (MAGI) cells and explore the mechanisms by which miR-217 influenced Tat-induced HIV-1 transactivation through down-regulation of SIRT1 expression. We showed that miR-217 was up-regulated when Tat was expressed in multinuclear activation of galactosidase indicator cells. Forced expression of "miR-217 mimics" increased Tat-induced LTR transactivation. In addition, miR-217 significantly inhibited SIRT1 protein expression by acting on the 3'-UTR of the SIRT1 mRNA. In turn, the decrease in SIRT1 protein abundance provoked by miR-217 affected two important types of downstream signaling molecules that were regulated by Tat. Lower expression of SIRT1 caused by miR-217 enhanced Tat-induced phosphorylation of IKK and p65-NFkB and also exacerbated the loss of AMPK phosphorylation triggered by Tat. Our results uncover previously unknown links between Tat and a specific host cell miRNA that targets SIRT1. We also demonstrate that this regulatory mechanism impinges on p65-NFkB and AMPK signaling: two important host cell pathways that influence HIV-1 pathogenesis. Our results also suggest that strategies to augment SIRT1 protein expression by down-regulation of miR-217 may have therapeutic benefits to prevent HIV-1 replication.
authors.affiliation: College of Life Science and Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing, China. zhanghs@bjut.edu.cn
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Zhang
authors.forename: Tong-Chao
authors.initials: TC
authors.lastname: Wu
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Sang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ruan
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D004789:Enzyme Activation; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C553315:MIRN217 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D054322:tat Gene Products, Human Immunodeficiency Virus; D000263:Adenylate Kinase; C447939:SIRT1 protein, human; D056564:Sirtuin 1