Abstract
Gammaherpesviruses, including the human pathogens Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), establish lifelong latent infection in B cells and are associated with a variety of tumors. In addition to protein coding genes, these viruses encode numerous microRNAs (miRNAs) within their genomes. While putative host targets of EBV and KSHV miRNAs have been previously identified, the specific functions of these miRNAs during in vivo infection are largely unknown. Murine gammaherpesvirus 68 (MHV68) is a natural pathogen of rodents that is genetically related to both EBV and KSHV, and thus serves as an excellent model for the study of EBV and KSHV genetic elements such as miRNAs in the context of infection and disease. However, the specific targets of MHV68 miRNAs remain completely unknown. Using a technique known as qCLASH (quick crosslinking, ligation, and sequencing of hybrids), we have now identified thousands of Ago-associated, direct miRNA-mRNA interactions during lytic infection, latent infection and reactivation from latency. Validating this approach, detailed molecular analyses of specific interactions demonstrated repression of numerous host mRNA targets of MHV68 miRNAs, including Arid1a, Ctsl, Ifitm3 and Phc3. Notably, of the 1,505 MHV68 miRNA-host mRNA targets identified in B cells, 86% were shared with either EBV or KSHV, and 64% were shared among all three viruses, demonstrating significant conservation of gammaherpesvirus miRNA targeting. Pathway analysis of MHV68 miRNA targets further revealed enrichment of cellular pathways involved in protein synthesis and protein modification, including eIF2 Signaling, mTOR signaling and protein ubiquitination, pathways also enriched for targets of EBV and KSHV miRNAs. These findings provide substantial new information about specific targets of MHV68 miRNAs and shed important light on likely conserved functions of gammaherpesvirus miRNAs.
Highlights
Gammaherpesviruses are a family of large double-stranded DNA viruses that establish lifelong latent infections in their hosts
Of the 1,505 Murine gammaherpesvirus 68 (MHV68) miRNA-host mRNA targets identified in B cells, 86% were shared with either Epstein-Barr virus (EBV) or Kaposi’s sarcoma-associated herpesvirus (KSHV), and 64% were shared among all three viruses, demonstrating significant conservation of gammaherpesvirus miRNA targeting
Pathway analysis of MHV68 miRNA targets further revealed enrichment of cellular pathways involved in protein synthesis and protein modification, including eIF2 Signaling, mTOR signaling and protein ubiquitination, pathways enriched for targets of EBV and KSHV miRNAs
Summary
Gammaherpesviruses are a family of large double-stranded DNA viruses that establish lifelong latent infections in their hosts. This group includes the human pathogens Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), as well as murine gammaherpesvirus 68 (MHV68, MuHV-4, γHV68). These viruses gain an initial foothold in the host by replicating in epithelial cells at the site of inoculation, and subsequently establish lifelong latent infection in the periphery in circulating B cells. MiRNAs integrate into the RNAinduced silencing complex (RISC), and are directed to target mRNAs through partial sequence complementarity [6]. In the context of RISC, the miRNA-mRNA binding interaction can result in mRNA silencing through translational repression or cleavage of the mRNA target [7,8]
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