Date Published: November 19, 2015
Publisher: Public Library of Science
Author(s): John Karijolich, Emma Abernathy, Britt A. Glaunsinger, Erle S. Robertson.
Short interspersed nuclear elements (SINEs) are highly abundant, RNA polymerase III-transcribed noncoding retrotransposons that are silenced in somatic cells but activated during certain stresses including viral infection. How these induced SINE RNAs impact the host-pathogen interaction is unknown. Here we reveal that during murine gammaherpesvirus 68 (MHV68) infection, rapidly induced SINE RNAs activate the antiviral NF-κB signaling pathway through both mitochondrial antiviral-signaling protein (MAVS)-dependent and independent mechanisms. However, SINE RNA-based signaling is hijacked by the virus to enhance viral gene expression and replication. B2 RNA expression stimulates IKKβ-dependent phosphorylation of the major viral lytic cycle transactivator protein RTA, thereby enhancing its activity and increasing progeny virion production. Collectively, these findings suggest that SINE RNAs participate in the innate pathogen response mechanism, but that herpesviruses have evolved to co-opt retrotransposon activation for viral benefit.
While only ~1.5% of mammalian genomes consist of protein coding sequence, upwards of 75% of the genome is transcribed [1, 2]. A considerable amount of this transcription generates stable non-protein-coding RNAs (ncRNAs) of potential biological relevance. Similarly, transcription from the genomes of many large double stranded (ds) DNA viruses is pervasive and can generate an abundance of long and short ncRNAs, a number of which have key roles in viral replication and pathogenesis [3–11]. While there is an increasing appreciation that viruses have adopted ncRNAs as part of their gene regulatory repertoire, with the exception of some small ncRNAs such as microRNAs, how most other cellular ncRNAs may impact the gene expression landscape during infection remains unknown. Given that viruses have provided significant insight into mammalian gene regulation, they have the potential to reveal new features of ncRNA biology.
Here, we demonstrate that MHV68-induced activation of SINE RNA serves to regulate viral and cellular gene expression through distinct mechanisms (Fig 7). SINE RNAs reside in the nucleus and in the cytoplasm, and participate in gene regulation in both compartments. Nuclear SINE RNAs appear absent from viral promoters but associate with specific cellular promoters that are repressed upon SINE activation, while SINE RNAs in the cytoplasm drive activation of the antiviral NF-κB signaling pathway. Though this pathway is normally detrimental to viral replication, MHV68 co-opts the IKKβ component of the NF-κB cascade to boost the activity of the viral lytic transactivator RTA, thereby enhancing viral gene expression and replication . Thus, beyond direct regulation of cellular gene expression, induction of this class of ncRNAs may be linked to early immune-based sensing of infection, a process that has been hijacked by gammaherpesviruses to enhance viral gene expression.