Kaposi's Sarcoma Virus and Virus - Host Protein Interaction
Research in our lab is focused on understanding how the interplay between viral and cellular proteins results in altered patterns of gene expression in the infected cells, as well as the advantage that these changes confer during viral replication. Most of our studies involve Kaposi’s sarcoma-associated herpesvirus (KSHV), a large DNA virus of the gammaherpesvirus subfamily that causes Kaposi’s sarcoma and some aggressive lymphomas in individuals with compromised immune systems. KSHV was discovered during the early days of the AIDS epidemic because Kaposi’s sarcoma is a common opportunistic illness among untreated AIDS patients. To date KSHV remains an important cause of cancer morbidity and mortality in parts of Africa. Like other herpesviruses, KSHV can infect cells both in a dormant (latent) fashion or in a replicative (lytic) fashion. While latently infected cells constitute the tumor mass, lytically infected cells secrete paracrine factors that sustain the tumor. Thus, both parts of the life cycle are important for the disease. KSHV encodes at least 90 genes, a third of which are thought to contribute to virus-host interactions. We are focusing on viral genes that change host gene expression in a broad way.
Figure 1. KSHV - Host Cell Interaction.
New regulators of gene expression in KSHV
To identify new gene regulators in KSHV we screened 89 different KSHV proteins for their ability to change expression of an exogenous reporter. Several KSHV proteins with no known role in gene expression were found to either suppress or boost gene expression. Some of the proteins may act at the level of RNA biogenesis, while others directly regulate protein levels. These novel functions may be conserved among gammaherpesviruses, as homologs of the candidate regulators in MHV68, a related mouse virus, also modulate gene expression. We are currently investigating how several of these putative regulators interact with cellular pathways and what genes they affect using viral mutants.
The unexpected specificity of the KSHV SOX RNase
The viral RNase SOX is a known regulator of gene expression in KSHV. It induces widespread destruction of mRNAs by cutting the RNAs internally and exploiting cellular enzymes to degrade the fragments thus created. While studying the mechanism of action of SOX, we made the unexpected finding that SOX cuts RNAs at specific locations defined by currently unknown sequence elements (Covarrubias, Gaglia et al. 2011). This mechanism would explain why mRNAs are differentially sensitive to degradation by SOX cleavage and raises the intriguing possibility that this specificity provides an additional level of regulation in the control of host gene expression. We are using high-throughput sequencing to identify the sequences that guide SOX’s specificity in order to understand the action of this protein in more detail. We are also interested in investigating the specificity of RNases from other viruses that perform a similar function to SOX.