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Uncovering the Role of Global mRNA Degradation during the Gammaherpesvirus Lifecycle

  • Author(s): Richner, Justin Michael
  • Advisor(s): Glaunsinger, Britt A
  • et al.
Abstract

The human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's Sarcoma-associated herpesvirus (KSHV) are very common in the human population and cause a number of diseases. During a lytic infection, these viruses block host gene expression through the global mRNA degradation activity of the viral proteins BGLF5 and SOX, in EBV and KSHV respectively. Despite significant advancements in understanding the mechanism of this process, termed host shutoff, little is known regarding the contribution of this activity towards the viral lifecycle, predominately due to experimental difficulties in studying these viruses. In this study, we aimed to uncover the role of host shutoff during a gammaherpesviral infection using the related murine gammaherpesvirus 68 (MHV68) as a model. Unlike EBV or KSHV, MHV68 has a tractable genetic system and readily available animal model. We first verified that the properties of host shutoff are conserved across KSHV, EBV, and MHV68. We then confirmed that host shutoff during MHV68 infection is executed by its SOX homolog, here termed muSOX. Deletion of muSOX from the viral genome resulted in a virus unable to replicate, likely due to the multi-functional nature of muSOX and its homologs. We therefore performed site-directed and random mutagenesis screens to identify mutants of muSOX which lacked host shutoff activity, but still retained its other known functions. We identified a single amino acid point mutant with the desired characteristics and introduced this mutant into the viral genome. The resulting virus caused significantly less mRNA degradation and host shutoff, yet was still viable for replication. By investigating the properties of infections with the mutant virus, we found host shutoff to be dispensable for lytic replication yet critical for latency establishment. These findings, for the first time, identify host shutoff as an important factor in the gammaherpesvirus lifecycle and link two distinct stages of the viral lifecycle, lytic replication and latency. Furthermore these findings suggest that the global manipulation of gene expression promotes a successfully lifelong gammaherpesvirus infection.

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