Abstract
Hepes simplex Virus type 1 (HSV-1) is an enveloped DNA virus that can cause lytic and latent infection. miRNAs post-transcriptionally regulate gene expression, and our previous work has indicated that HSV-1 infection induces miR-101 expression in HeLa cells. The present study demonstrates that HSV-1-induced miR-101 is mainly derived from its precursor hsa-mir-101-2, and the HSV-1 immediate early gene ICP4 (infected-cell polypeptide 4) directly binds to the hsa-mir-101-2 promoter to activate its expression. RNA-binding protein G-rich sequence factor 1 (GRSF1) was identified as a new target of miR-101; GRSF1 binds to HSV-1 p40 mRNA and enhances its expression, facilitating viral proliferation. Together, ICP4 induces miR-101 expression, which downregulates GRSF1 expression and attenuates the replication of HSV-1. This allows host cells to maintain a permissive environment for viral replication by preventing lytic cell death. These findings indicate that HSV-1 early gene expression modulates host miRNAs to regulate molecular defense mechanisms. This study provides novel insight into host-virus interactions in HSV-1 infection and may contribute to the development of antiviral therapeutics.
Highlights
Hepes simplex Virus type 1 (HSV-1) is an enveloped DNA virus that can cause lytic and latent infection. miRNAs post-transcriptionally regulate gene expression, and our previous work has indicated that HSV-1 infection induces miR-101 expression in HeLa cells
Infected-cell polypeptide 4 (ICP4) binds to the proximal human vascular endothelial growth factor (VEGF)-A promoter and sufficient to promote VEGF-A transcription; this process requires a tract of GC-rich sequences in the VEGF-A promoter, which is similar to the promoters for the HSV-1 E genes that are normally transactivated by ICP4
The life cycle of HSV-1 begins when cells are first invaded by HSV-1, at which point lytic and replicative infection begins and many more viral particles are produced, leading to cell death the virions released to the surrounding cells or tissues, and they switch to latent infection mode[31]
Summary
Xiangling Wang*, Caifeng Diao*, Xi Yang, Zhen Yang, Min Liu, Xin Li & Hua Tang received: 06 November 2015 accepted: 25 February 2016 Published: 17 March 2016. The RNA expression levels of RCL1, the hsa-mir-101-2 precursor and mature miR-101 were found to be highly induced or reduced under ICP4 overexpression or knockdown conditions respectively (Fig. 3C,D) Taken together, these data indicate that ICP4 activates the miR-101-2/RCL1 promoter to induce the expression of miR-101 during HSV-1 infection. The mRNA and protein expression levels of GRSF1 were significantly reduced under HSV-1 infection or ICP4 overexpression but were greatly increased under ICP4 knockdown conditions (Fig. 4E,F) These results indicate that miR-101 directly binds to the 3′ UTR of GRSF1 mRNA, reduces target gene expression, and plays an important role in the suppression of GRSF1 during HSV-1 infection. Immunofluorescence and western blot assays showed that GRSF1 overexpression enhanced, but knockdown significantly decreased the expression levels of HSV-1 glycoprotein (Fig. 5D) and HSV-1 capsid protein p40 (Fig. 5E) Together, these results indicate that GRSF1, a target of miR-101, promotes HSV-1 proliferation. These results demonstrate that GRSF1 protein directly binds to p40 mRNA to enhance its translation
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