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The conserved herpesviral kinase ORF36 activates B2 retrotransposons during murine gammaherpesvirus infection

View ORCID ProfileAaron M. Schaller, View ORCID ProfileJessica Tucker, Ian Willis, View ORCID ProfileBritt A. Glaunsinger
doi: https://doi.org/10.1101/2020.01.06.895789
Aaron M. Schaller
1Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, United States of America
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Jessica Tucker
2Department of Plant & Microbial Biology, University of California Berkeley, Berkeley, CA, United States of America
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Ian Willis
3Departments of Biochemistry and Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY, United States of America
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Britt A. Glaunsinger
1Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, United States of America
2Department of Plant & Microbial Biology, University of California Berkeley, Berkeley, CA, United States of America
4Howard Hughes Medical Institute, Berkeley, CA, United States of America
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  • For correspondence: glaunsinger@berkeley.edu
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ABSTRACT

Short interspersed nuclear elements (SINEs) are RNA polymerase III (RNAPIII) transcribed, retrotransposable noncoding RNA (ncRNA) elements ubiquitously spread throughout mammalian genomes. While normally silenced in healthy somatic tissue, SINEs can be induced during infection with DNA viruses, including the model murine gammaherpesvirus MHV68. Here, we explored the mechanisms underlying MHV68 activation of SINE ncRNAs. We demonstrate that lytic MHV68 infection of B cells, macrophages and fibroblasts leads to robust activation of the B2 family of SINEs in a cell autonomous manner. B2 ncRNA induction requires neither host innate immune signaling factors nor involvement of the RNAPIII master regulator Maf1. However, we identify MHV68 ORF36, the conserved herpesviral kinase, as playing a key role in B2 induction during lytic infection. SINE activation is linked to ORF36 kinase activity and can also be induced by HDAC1/2 inhibition, which is one of the known ORF36 functions. Collectively, our data suggest that ORF36-mediated changes in chromatin modification contribute to B2 activation during MHV68 infection, and that this activity is conserved in other herpesviral protein kinase homologs.

AUTHOR SUMMARY Viral infection dramatically changes the levels of many types of RNA in a cell. In particular, certain oncogenic viruses activate expression of repetitive genes called retrotransposons, which are normally silenced due to their ability to copy and spread throughout the genome. Here, we established that infection with the gammaherpesvirus MHV68 leads to a dramatic induction of a class of noncoding retrotransposons called B2 SINEs in multiple cell types. We then explored how MHV68 activates B2 SINEs, revealing a role for the conserved herpesviral protein kinase ORF36. Both ORF36 kinase-dependent and kinase-independent functions contribute to B2 induction, perhaps through ORF36 targeting of proteins involved in controlling the accessibility of chromatin surrounding SINE loci. Understanding features underlying induction of these elements following MHV68 infection should provide insight into core elements of SINE regulation, as well as dis-regulation of SINE elements associated with disease.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 06, 2020.
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The conserved herpesviral kinase ORF36 activates B2 retrotransposons during murine gammaherpesvirus infection
Aaron M. Schaller, Jessica Tucker, Ian Willis, Britt A. Glaunsinger
bioRxiv 2020.01.06.895789; doi: https://doi.org/10.1101/2020.01.06.895789
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The conserved herpesviral kinase ORF36 activates B2 retrotransposons during murine gammaherpesvirus infection
Aaron M. Schaller, Jessica Tucker, Ian Willis, Britt A. Glaunsinger
bioRxiv 2020.01.06.895789; doi: https://doi.org/10.1101/2020.01.06.895789

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