Abstract
Lytic gammaherpesvirus infection restricts host gene expression by promoting widespread degradation of cytoplasmic mRNA through the activity of the viral endonuclease SOX. Though generally assumed to be selective for cellular transcripts, the extent to which SOX impacts viral mRNA stability has remained unknown. We addressed this issue using the model murine gammaherpesvirus MHV68 and, unexpectedly, found that all stages of viral gene expression are controlled through mRNA degradation. Using both comprehensive RNA expression profiling and half-life studies we reveal that the levels of the majority of viral mRNAs but not noncoding RNAs are tempered by MHV68 SOX (muSOX) activity. The targeting of viral mRNA by muSOX is functionally significant, as it impacts intracellular viral protein abundance and progeny virion composition. In the absence of muSOX-imposed gene expression control the viral particles display increased cell surface binding and entry as well as enhanced immediate early gene expression. These phenotypes culminate in a viral replication defect in multiple cell types as well as in vivo, highlighting the importance of maintaining the appropriate balance of viral RNA during gammaherpesviral infection. This is the first example of a virus that fails to broadly discriminate between cellular and viral transcripts during host shutoff and instead uses the targeting of viral messages to fine-tune overall gene expression.
Highlights
Viruses use a variety of mechanisms to dampen host gene expression, including inhibiting cap-dependent translation, transcription, splicing, and promoting host mRNA degradation
Gammaherpesviruses promote host shutoff by inducing widespread mRNA degradation, a process initiated by the viral SOX nuclease
We reveal that during infection with the murine gammaherpesvirus MHV68, the majority of viral transcripts of all kinetic classes are broadly down regulated through the activity of the MHV68 SOX protein
Summary
Viruses use a variety of mechanisms to dampen host gene expression, including inhibiting cap-dependent translation, transcription, splicing, and promoting host mRNA degradation. The presumed viral benefits of this ‘host shutoff’ phenotype include reduced competition for gene expression machinery and resources, as well as impaired immune responses through decreasing host factors involved in sensing infection. The importance of this phenotype in vivo has been directly confirmed for both alpha- and gammaherpesviruses, where host shutoff mutants exhibit defects in immune evasion (in the case of the herpes simplex viruses HSV-1 and HSV-2), viral trafficking, and latency establishment [1,2,3]. SARS coronavirus causes host shutoff by promoting endonucleolytic cleavage of cellular mRNAs, but its viral mRNAs bear a protective 59 leader sequence that prevents their cleavage [13]
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