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FUNCTIONAL PROTEOMICS: HUMAN CARBOXYLESTERASE I PROMOTES HEPATITIS C REPLICATION
DR Blais, JP Pezacki
Steacie Institute for Molecular Sciences, National Research Council, Ottawa, ON
In this proteomics era, chemical tools are needed for investigating the roles and interactions of proteins in complex biological systems to provide unique insights into the molecular mechanisms of disease. Given the obvious global health issue presented by hepatitis C virus (HCV), with more than 200 million infected individuals worldwide, there is great interest in elucidating the role of host and viral proteins in propagation, especially since very few therapeutics of clinical significance have been developed and no vaccines are currently available. Activity-based protein profiling (ABPP) experiments using a rhodamine-conjugated fluorophosphonate probe were performed to understand the fundamental aspects of HCV replication in liver cells. Using this probe, we have identified a number of differentially active proteins in cell culture model of HCV. One protein candidate, liver carboxylesterase 1 (CES1), was determined to have an increased enzymatic activity in liver cells harboring HCV replication. Our results indicate that the level of expression of CES1 influences HCV replication both positively and negatively. By being involved in cholesterol esterification and in the hydrolysis of drugs containing amine- and ester-bonds in the ER, this serine hydrolase might play a role in the formation of the membranous web HCV replication complex or the trafficking of HCV protein from the ER to the membranous web.