A Baculovirus-Encoded MicroRNA (miRNA) Suppresses Its Host miRNA Biogenesis by Regulating the Exportin-5 Cofactor Ran

Abstract

MicroRNAs have emerged as key players in the regulation of various biological processes in eukaryotes, including host-pathogen interactions. Recent studies suggest that viruses encode miRNAs to manipulate their host gene expression to ensure their effective proliferation, whereas the host limits virus infection by differentially expressing miRNAs that target essential viral genes. Here, we demonstrate that an insect virus, Bombyx mori nucleopolyhedrosis virus (BmNPV), modulates the small-RNA-mediated defense of its host, B. mori, by encoding an miRNA (bmnpv-miR-1) that downregulates the expression of the host GTPbinding nuclear protein Ran, an essential component of the exportin-5-mediated nucleocytoplasmic transport machinery mainly involved in small-RNA transport from the nucleus to the cytoplasm. We demonstrate the sequence-dependent interaction of bmnpv-miR-1 with Ran mRNA using cell culture and in vivo assays, including RNA interference (RNAi) of Ran. Our results clearly show that bmnpv-miR-1 represses Ran, leading to reduction in the host small-RNA population, and consequently, the BmNPV load increases in the infected larvae. Blocking of bmnpv-miR-1 resulted in higher expression levels of Ran and a decrease in BmNPV proliferation. In contrast, blockage of host miRNA, bmo-miR-8, which targets the immediate-early gene of the virus and whose production was repressed upon bmnpv-miR-1 and Ran dsRNA administration, resulted in a significant increase in the virus load in the infected B. mori larvae. The present study provides an insight into one of the evasion strategies used by the virus to counter the host defense for its effective proliferation and has relevance to the development of insect virus control strategies.

Temporal expression profiling of novel Spodoptera litura nucleopolyhedrovirus-encoded microRNAs upon infection of Sf21 cells

“…Recent insights into the function of baculoviral miRNAs have revealed interesting revelations about the stratagem of these viruses. Bombyx mori nucleopolyhedrovirus-encoded bmnpv-miR-1 was found to downregulate the expression of host nuclear protein Ran involved in exportin 5-mediated small RNA transport machinery (Singh et al, 2012), whilst bmnpvmiR-3 was found to be expressed during the early phase of infection and decrease the expression of baculoviral DNAbinding protein P6.9 (Singh et al, 2014). Autographa californica multiple nucleopolyhedrovirus (AcMNPV)-encoded AcMNPV-miR-1 was found to target viral gene ODV-E25, favouring the generation of occlusion-derived virions (Zhu et al, 2013).…”

Silencing of Host Genes Directed by Virus-Derived Short Interfering RNAs in Caenorhabditis elegans

“…miRNAs carried by both DNA and RNA viruses can also modulate host gene expression, thereby facilitating virus infection in the animal kingdom (5,18,41). Since miRNAs and siRNAs use similar factors for their biogenesis and function, it will be of great interest to see whether viRNAs can modulate host gene expression and thereby facilitate virus infection in the animal kingdom.…”

A MicroRNA Encoded by Autographa californica Nucleopolyhedrovirus Regulates Expression of Viral Gene ODV-E25

“…Although virus-encoded miRNAs have been described in mammalian viruses, such as Epstein-Barr virus (2) and simian virus 40 (3), the miRNAs encoded by baculovirus, which infect numerous beneficial insects and agricultural pests, have only been investigated in Bombyx mori nucleopolyhedrosis virus (BmNPV) (4,5). Investigation of the miRNAs encoded by these viruses would help to explain the role of miRNAs in host-pathogen interactions.…”