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Persistent Infection of Simian Foamy Virus Derived from the Japanese Macaque Leads to the High-Level Expression of microRNA that Resembles the miR-1 microRNA Precursor Family.

ABSTRACT: MicroRNAs (miRNAs) are a group of small non-coding RNAs that suppress the expression of target mRNAs. The seed sequence of miRNA plays a crucial role in recognizing the 3'-untranslated region of the target mRNA. Cells infected with a simian foamy virus (SFV) isolated from an African green monkey (Chlorocebus aethiops) (SFVcae) showed high expression levels of viral miRNAs encoded in the long terminal repeat of SFVcae. In the present study, we investigated the roles and expression of miRNAs derived from an SFV isolated from a Japanese macaque (Macaca fuscata) (SFVmfu) using next-generation sequencing technologies. The results obtained showed that SFVmfu also expressed viral miRNAs; however, the seed sequences of most miRNAs derived from SFVmfu differed from those reported previously from SFVcae. Cells persistently infected with SFVmfu strongly expressed an miRNA with the same seed sequence as the miR-1 microRNA precursor family. Luciferase reporter assays indicated that this miRNA down-regulates the expression of adenylyl cyclase-associated protein 1, which is up-regulated in several solid tumors. The present results suggest that SFVmfu utilizes viral miRNAs to establish long-term co-existence with the Japanese macaque.

SUBMITTER: Hashimoto-Gotoh A

PROVIDER: S-EPMC7104284 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Persistent Infection of Simian Foamy Virus Derived from the Japanese Macaque Leads to the High-Level Expression of microRNA that Resembles the miR-1 microRNA Precursor Family.

Hashimoto-Gotoh Akira A Kitao Koichi K Miyazawa Takayuki T

Microbes and environments 20200101 1

MicroRNAs (miRNAs) are a group of small non-coding RNAs that suppress the expression of target mRNAs. The seed sequence of miRNA plays a crucial role in recognizing the 3'-untranslated region of the target mRNA. Cells infected with a simian foamy virus (SFV) isolated from an African green monkey (Chlorocebus aethiops) (SFVcae) showed high expression levels of viral miRNAs encoded in the long terminal repeat of SFVcae. In the present study, we investigated the roles and expression of miRNAs deriv ...[more]

PMID: 31969530

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Project description:UnlabelledJapanese macaque (JM) rhadinovirus (JMRV) is a novel, gamma-2 herpesvirus that was recently isolated from JM with inflammatory demyelinating encephalomyelitis (JME). JME is a spontaneous and chronic disease with clinical characteristics and immunohistopathology comparable to those of multiple sclerosis in humans. Little is known about the molecular biology of JMRV. Here, we sought to identify and characterize the small RNAs expressed during lytic JMRV infection using deep sequencing. Fifteen novel viral microRNAs (miRNAs) were identified in JMRV-infected fibroblasts, all of which were readily detectable by 24 h postinfection and accumulated to high levels by 72 h. Sequence comparisons to human Kaposi's sarcoma-associated herpesvirus (KSHV) miRNAs revealed several viral miRNA homologs. To functionally characterize JMRV miRNAs, we screened for their effects on nuclear factor kappa B (NF-κB) signaling in the presence of two proinflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). Multiple JMRV miRNAs suppressed cytokine-induced NF-κB activation. One of these miRNAs, miR-J8, has seed sequence homology to members of the cellular miR-17/20/106 and miR-373 families, which are key players in cell cycle regulation as well as inflammation. Using reporters, we show that miR-J8 can target 3' untranslated regions (UTRs) with miR-17-5p or miR-20a cognate sites. Our studies implicate JMRV miRNAs in the suppression of innate antiviral immune responses, which is an emerging feature of many viral miRNAs.ImportanceGammaherpesviruses are associated with multiple diseases linked to immunosuppression and inflammation, including AIDS-related cancers and autoimmune diseases. JMRV is a recently identified herpesvirus that has been linked to JME, an inflammatory demyelinating disease in Japanese macaques that mimics multiple sclerosis. There are few large-animal models for gammaherpesvirus-associated pathogenesis. Here, we provide the first experimental evidence of JMRV miRNAs in vitro and demonstrate that one of these viral miRNAs can mimic the activity of the cellular miR-17/20/106 family. Our work provides unique insight into the roles of viral miRNAs during rhadinovirus infection and provides an important step toward understanding viral miRNA function in a nonhuman primate model system.

Project description:Simian and human foamy viruses (HFV and SFV), genetically related members of the spumavirus genus of retroviruses, have complex genome structures which encode the gag, pol, and env genes for virion proteins as well as additional open reading frames. One of these open reading frames is a viral transactivator, encoded by genes designated taf for SFV and bel-1 for HFV, which augments transcription directed by the long terminal repeat (LTR) through cis-acting targets in the U3 domain of the LTR. Recently, an internal transcriptional promoter has been identified in sequences within the 3' end of the HFV env gene (M. Lochelt, W. Muranyi, and R. M. Flugel, Proc. Natl. Acad. Sci. 90:7317-7321, 1993). We have demonstrated by using transient expression assays in several tissue culture cell lines and by analyzing viral transcripts in infected cells that SFV-1 from a rhesus macaque and SFV-3 from an African green monkey also encode an internal promoter in the env gene. Transcription directed by the internal promoters of SFV-1 and SFV-3 is activated by the taf-1 and taf-3 gene products, respectively, in several cell types. The importance of a TATA box for the SFV-1 internal promoter was established by site-specific mutagenesis, and the 5' ends of transcripts initiating in the internal promoter have been determined. cis-acting sequences in the SFV-1 env gene required for the response to taf-1 are contained within a 121-bp element located 5' to the TATA box in the internal promoter. This taf-1-responsive element in the internal promoter functions in a position- and orientation-independent fashion in a heterologous promoter and thus has the properties of an enhancer which depends on taf-1 activity. Alignments reveal that the SFV-1 internal promoter and the SFV-1 LTR have little sequence relatedness. Cross-transactivation studies show that the transactivators of SFV-1 and HFV function on the internal promoter and LTR of the homologous virus but not on the heterologous virus. In summary, the genomes of simian and human foamy viruses direct viral transcription through both the promoter in the LTR and an internal promoter within the env gene, and each promoter contains unique enhancer-like elements regulated by the viral transactivator.

Dataset Information

Persistent Infection of Simian Foamy Virus Derived from the Japanese Macaque Leads to the High-Level Expression of microRNA that Resembles the miR-1 microRNA Precursor Family.

Publications

Persistent Infection of Simian Foamy Virus Derived from the Japanese Macaque Leads to the High-Level Expression of microRNA that Resembles the miR-1 microRNA Precursor Family.

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