Sunday, October 1, 2023
10/1/2023
Most viral infections invoke major changes in host gene expression as part of a broader strategy to create an optimal environment for viral replication. By suppressing host protein synthesis, viruses repurpose the biosynthetic resources of the host cell to maximize the accumulation of viral proteins or nucleic acids and thus ultimately boost the yield of new infectious progeny. Herpes simplex virus type 1 (HSV-1) provides a prime example of this important ‘host shutoff’ phenomenon. HSV-1 infection is accompanied by widescale disruption of host mRNA biogenesis through dysregulation of transcription by RNA polymerase II coupled with changes in mRNA stability, splicing, 3’-end formation, and transcription termination. Although multiple studies have implicated the essential viral regulatory protein ICP27 in aspects of shutoff by HSV-1, the exact mechanisms and their relative contributions remain to be elucidated. Recently, we demonstrated that HSV-1 infection induces widespread changes in the subcellular localization of host nuclear factors required for the installation, removal and recognition of internal RNA modifications including methylation at the N6-position of adenosine (m6A). This results in global reductions in the internal base modifications present on both host and viral RNAs. Importantly, we identified the essential viral regulatory protein ICP27 as both necessary and sufficient for this striking effect. Internal RNA modifications such as m6A influence many aspects of mRNA and lncRNA biogenesis including recognition of hardwired splicing and cleavage/polyadenylation signals, and m6A also regulates the export, stability and translation of mature mRNAs. We observed that viral gene expression is sensitive to loss of m6A at the beginning of the infection cycle but is less impacted at later times, coincident with reduced RNA modification frequency. Drawing these observations together we propose that the poorly understood ability of ICP27 to broadly disrupt host gene expression is mediated, at least in part, by its ability to redefine the epigenetic landscape of the host transcriptome. To understand this better, we will more fully characterize the impact of ICP27 expression on the host machinery responsible for RNA chemical modification and for 3’-end processing and transcription termination. Recent studies reveal a mechanistic linkage between the sites of m6A placement and use of nearby polyadenylation and signals and we hypothesize that this is exploited by ICP27 to bring about a widescale disruption of transcription termination (DoTT) that preferentially impacts the host transcriptome in HSV-1 infected cells. To understand why 3’-end formation of HSV-1 mRNAs is largely insensitive to ICP27- mediated DoTT, we will profile m6A installation across the viral transcriptome to determine the impact of m6A on cleavage and polyadenylation site usage within viral transcription units.
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