Elucidating new pro and anti-viral mechanisms using the budding yeast Saccharomyces cerevisiae.
The ubiquitous host-virus arms race has led to the evolution of diverse anti-viral mechanisms across all taxa. In recent years, newly characterized anti-viral systems have been found to be remarkably conserved from bacteria to mammals, revealing the potential to gain a unique insight into these systems through the study of simple microbial organisms. Surprisingly, budding yeast, a key eukaryotic microbial model organism, has been minimally exploited for the study of viruses and anti-viral systems even though it is chronically infected with a double-stranded RNA virus called L-A. We discovered that L-A is attenuated by a novel anti-viral pathway requiring Nuc1, a mitochondrial DNA/RNA endonuclease homologous to endonuclease G (EndoG), which is most well-known for its role in mammalian apoptosis. We found that NUC1 collaborates with other established anti-viral systems to prevent rampant L-A proliferation, which causes lethality at high temperatures. Thus, L-A is deleterious for the host, and it must be attenuated to prevent lethal pathogenesis. Leveraging these discoveries, we elucidated L-A induced proteotoxic stress as the basis for its lethal pathogenesis and used genetic screens to identify numerous additional viral attenuation factors. These factors distinguish disparate collaborative mechanisms of viral innate immunity involving both the mitochondria and the translational machinery. Our ongoing efforts employ molecular, cellular, genetic, and functional genomic approaches to identify and characterize new mechanisms of viral attenuation.
- MGY420: Regulation of Gene Expression
- MGY480: Special Research Project
- Graduate topics course: Epigenetics & Transcriptional Control