Key Host Factors Co-Opted to Form Viral Replication Organelles

Plus-­stranded RNA viruses, which cause major losses in agriculture and pose significant risks to human health, depend heavily on co-­opted host factors to replicate in infected cells. RNA viruses subvert host subcellular membranes to build replication organelles that multiply their RNA genomes in the cytosol of infected cells. The emerging picture with several viruses that the formation of replication organelles, which concentrate viral and host components and provide protection against antiviral responses, is critical for virus replication. Yet, it is a long-­standing unanswered question is how replication organelles are formed. A breakthrough in this area is the identification of Sac1 lipid phosphatase, Fis1 mitochondrial fission protein and Atg11 autophagy scaffold protein as key host factors in tombusvirus replication, thus serving as outstanding targets for new antiviral approaches. This proposal is based on the central roles of Sac1, Fis1 and Atg11 in the generation of tombusvirus replication organelles. The PI will identify the functions of Sac1, Fis1 and Atg11 based on the awesome power of yeast genetics in combination with cell-­free replication assays, and elegant biochemical assays with the purified viral replicase developed for tombusviruses by the PI. Similar work will be extended to TBSV-­plant infections, which will likely lead to major new insights into RNA virus replication and viral pathogenesis. Developing an efficient antiviral strategy based on blocking the function of co-­opted Sac1, Fis1 or Atg11 could rapidly be done in the elegant tombusvirus-­yeast/plant systems. This can then be followed by adapting the gained knowledge and methods for other animal, human and plant viruses. Findings from this work will likely transform our understanding of virus-­host interactions and will promote major research with plant, animal and human viruses. Inhibition of formation of critical viral replication organelles could be a powerful approach to block virus replication. Therefore, dissecting the functions of the co-­opted cellular Sac1 phosphatase and Fis1 and Atg11 during viral infections will facilitate the development of novel and possibly very potent and broad-­range antiviral approaches.