Exploring the Functions of Cytoplasmic Sirtuin 2 during Herpesvirus Infection

Abstract

Sirtuins (SIRTs) have gained prominence as key regulators of multiple biological processes. While most work on SIRTs has focused on SIRT regulation of cancer progression, calorie restriction and aging, SIRT control of transcriptional regulation through modification of histone and transcription factors also suggest SIRTs as possible modulators of host and viral gene expression during viral infection. Interestingly, recent work from our laboratory and others has established that siRNA mediated inhibition of each of the seven mammalian SIRTs correlates with increased viral titers for a number of DNA and RNA viruses, suggesting their use as effective targets for the development of broad-spectrum antiviral treatments. Among the tested viral infections, SIRTs displayed significant impact on human cytomegalovirus (HCMV) titers. However, the means through which SIRTs exert their functions during HCMV infection remain poorly understood. Here, I utilized a multidisciplinary approach integrating molecular virology and microscopy to assess the roles of the cytoplasmic SIRT2 during HCMV infection, and test whether HCMV replication is dependent on SIRT2 deacetylase activity. To obtain insight into the activity of SIRT2 during HCMV replication, I monitored viral protein levels, viral titers, and viral assembly in the presence of SIRT2 inhibition, either through shRNA-mediated SIRT2 knockdown (KD) or treatment with small molecule inhibitor AGK2. Overall, my studies demonstrate that inhibition of SIRT2 enzymatic activity impacts HCMV replication, though further studies are needed to elucidate the mechanism(s) through which SIRT2 acts during HCMV infection.