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.

MicroRNA-217, down-regulated in clear cell renal cell carcinoma and associated with lower survival, suppresses cell proliferation and migration

“…In cultured mouse AML-12 hepatocytes and in mouse livers, miR-217 promotes ethanol-induced fat accumulation by down-regulating SirT1 [16]. miR-217 also influences Tatinduced HIV-1 long terminal repeat (LTR) transactivation by down-regulation of SirT1 expression [17].It has been reported that miR-217 acts as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS [8]. Overexpression of miR-217 can reverse the malignant behavior of pancreatic ductal adenocarcinoma cells.…”

MicroRNAs and HIV-1: Complex Interactions

“…Independently, miR-17-5p and miR20a were found by a separate group to target p300/CBPassociated factor (PCAF), another cellular cofactor of the viral Tat protein (29), and a further set of six miRNAs (miR15a, miR-15b, miR-16, miR-20a, miR-93, and miR-106b) were reported to repress the expression of a third Tat cofactor, Pur-␣, which was noted also to be enriched in monocytes (45). In a converse example, Zhang et al (46) found that miR-217 was induced by Tat and that miR-217 increased HIV-1 expression by targeting SIRT-1 (sirtuin-1), a host protein that deacetylates and inactivates Tat function. Collectively, these discrete findings illustrate the complex miRNA-FIGURE 1.…”

The role of microRNAs in HIV infection

“…In the same years, Zhang et al found that miR-217 was induced by tat and that miR-217 increased HIV-1 expression by targeting SIRT-a (sirtuin-1), a host protein that deacetylates and inactivates tat function [53]. These findings, all together, illustrate the complex miRNAmediated positive and negative regulatory events that influence viral replication.…”