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Regulation of KSHV lytic switch protein expression by a virus-encoded microRNA: an evolutionary adaptation that fine-tunes lytic reactivation.

ABSTRACT: Herpesviruses encode numerous microRNAs (miRNAs), most of whose functions are unknown. The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 17 known miRNAs as part of its latency program, suggesting that these RNAs might function to regulate the latent state. Here we show that one of these KSHV miRNAs, miRK9( *), targets a sequence in the 3' untranslated region (UTR) of the mRNA encoding the major lytic switch protein (RTA), which controls viral reactivation from latency. Ectopic expression of miRK9( *) impairs RTA synthesis, while its specific antagonism in latently infected cells enhances spontaneous lytic reactivation frequency by 2- to 3-fold. Mutation of the recognition sequence in the RTA 3'UTR abolishes RTA downregulation by miRK9( *). We propose that miRNA targeting of RTA, while not the primary regulator of the lytic switch, functions like a safety mechanism on the trigger of lytic reactivation, preventing stochastic variations in basal RTA transcription from activating inappropriate entry into the lytic cycle.

SUBMITTER: Bellare P

PROVIDER: S-EPMC2822622 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Regulation of KSHV lytic switch protein expression by a virus-encoded microRNA: an evolutionary adaptation that fine-tunes lytic reactivation.

Bellare Priya P Ganem Don D

Cell host & microbe 20091201 6

Herpesviruses encode numerous microRNAs (miRNAs), most of whose functions are unknown. The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 17 known miRNAs as part of its latency program, suggesting that these RNAs might function to regulate the latent state. Here we show that one of these KSHV miRNAs, miRK9( *), targets a sequence in the 3' untranslated region (UTR) of the mRNA encoding the major lytic switch protein (RTA), which controls viral reactivation from latency. Ectopic expressio ...[more]

PMID: 20006845

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Project description:Kaposi's sarcoma associated herpesvirus (KSHV) persists in a highly-ordered chromatin structure inside latently infected cells with the majority of the viral genome having repressive marks. However, upon reactivation the viral chromatin landscape changes into 'open' chromatin through the involvement of lysine demethylases and methyltransferases. Besides methylation of lysine residues of histone H3, arginine methylation of histone H4 plays an important role in controlling the compactness of the chromatin. Symmetric methylation of histone H4 at arginine 3 (H4R3me2s) negatively affects the methylation of histone H3 at lysine 4 (H3K4me3), an active epigenetic mark deposited on the viral chromatin during reactivation. We identified a novel binding partner to KSHV viral DNA processivity factor, ORF59-a protein arginine methyl transferase 5 (PRMT5). PRMT5 is an arginine methyltransferase that dimethylates arginine 3 (R3) of histone H4 in a symmetric manner, one hallmark of condensed chromatin. Our ChIP-seq data of symmetrically methylated H4 arginine 3 showed a significant decrease in H4R3me2s on the viral genome of reactivated cells as compared to the latent cells. Reduction in arginine methylation correlated with the binding of ORF59 on the viral chromatin and disruption of PRMT5 from its adapter protein, COPR5 (cooperator of PRMT5). Binding of PRMT5 through COPR5 is important for symmetric methylation of H4R3 and the expression of ORF59 competitively reduces the association of PRMT5 with COPR5, leading to a reduction in PRMT5 mediated arginine methylation. This ultimately resulted in a reduced level of symmetrically methylated H4R3 and increased levels of H3K4me3 marks, contributing to the formation of an open chromatin for transcription and DNA replication. Depletion of PRMT5 levels led to a decrease in symmetric methylation and increase in viral gene transcription confirming the role of PRMT5 in viral reactivation. In conclusion, ORF59 modulates histone-modifying enzymes to alter the chromatin structure during lytic reactivation.

Dataset Information

Regulation of KSHV lytic switch protein expression by a virus-encoded microRNA: an evolutionary adaptation that fine-tunes lytic reactivation.

Publications

Regulation of KSHV lytic switch protein expression by a virus-encoded microRNA: an evolutionary adaptation that fine-tunes lytic reactivation.

Similar Datasets

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