Characterizing the Molecular Basis for mRNA Targeting and Destruction by the Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Protein SOX

Lytic infection with gamma herpesviruses such as Epstein Barr Virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) results in a global depletion of cellular mRNA, which manifests in a general suppression of host gene expression, termed host shutoff. The importance of targeting cellular gene expression at the posttranscriptional level is highlighted by the observation that many changes in important cellular gene programs result in drastic changes in RNA stability. Hence, virus targeting of host gene expression at this level likely represents an efficient way to change the cellular environment into one the supports maximal viral production. In KSHV, the host shutoff phenotype is caused by virally encoded multifunctional nuclease, SOX, that is conserved throughout all gamma-herpesviruses. Here I provide detailed mechanistic insight into how SOX targets host messages to enact host shutoff activity in cells. I show that with in the cytoplasm, SOX specifically targets conserved mRNA features, which normally promote their efficient expression. Furthermore, I demonstrate that this mechanism of mRNA targeting is conserved across various other viruses, likely demonstrating an evolutionarily convergent strategy. Characterizing how viruses co-op specific cellular factors involved in gene expression will yield a better understanding of the signals that initiate activation of RNA turnover pathways needed for viral replication success