UNCOVERING THE MULTIFACETED FUNCTIONS OF SIRTUIN 2 IN HUMAN HEALTH AND DISEASE

Abstract

SIRT2 is a cytoplasmic NAD+-deacetylase that regulates a diverse range of substrates and cellular processes through post-translational modifications. The extensive enzymatic functions of SIRT2 leads it to have important implications for human disease, including in cancer, neurodegenerative disease, and metabolic disorders. Recent work has found that SIRT2 also plays a role during viral infection, as inhibition of SIRT2 deacetylase activity was shown to suppress hepatitis B virus (HBV) replication. However, SIRT2 has not been studied in the context of other viral infections. Our group has previously demonstrated that throughout human cytomegalovirus (HCMV) infection, the viral and host proteomes are dynamically acetylated in order to regulate both host defense responses and viral replication. These findings suggest that SIRT2 deacetylation activity may contribute to HCMV replication. In chapter one, I review the substrates and enzymatic functions of SIRT2, highlighting its deacetylase, lipoamidase, deacylase, debenzoylation, and de-4-oxnononanoylation activities. Additionally, I summarize the significance of SIRT2 and its potential as a therapeutic target to treat two prominent human health concerns: neurological disorders and infectious disease. In chapter 2, I investigate how the inhibition of SIRT2 deacetylase activity impacts HCMV infection using the specific SIRT2 inhibitor, AGK2. Using molecular virology techniques and quantitative proteomics, I establish that inhibition of SIRT2 is antiviral and can effectively attenuate HCMV replication. Additionally, I discover that SIRT2 localizes to the cytoplasm throughout HCMV infection. By investigating temporal protein abundance changes and SIRT2 protein interactions, I provide insights into the underlying mechanisms of the antiviral activity of SIRT2 inhibition during HCMV infection. Altogether, this study identifies the antiviral properties of the SIRT2 deacetylase inhibitor, AGK2, and its potential as a therapeutic avenue for treating HCMV infection.