Activity-based protein profiling identifies a host enzyme, carboxylesterase 1, which is differentially active during...

Area of Science:

• Virology
• Hepatology
• Biochemistry

Background:

• Hepatitis C virus (HCV) requires host cell proteins and enzymatic modifications for replication.
• Identifying host enzymes crucial for viral propagation is essential for understanding HCV pathogenesis.

Purpose of the Study:

• To investigate the role of host serine hydrolases in HCV replication using activity-based protein profiling.
• To identify and characterize specific host enzymes that influence HCV propagation.

Main Methods:

• Activity-based protein profiling of serine hydrolases in HCV-replicating Huh7 cells.
• Silencing carboxylesterase 1 (CES1) using siRNA and assessing its impact on HCV replication.
• Analyzing HCV core protein levels, viral titers, and lipid droplet characteristics in response to CES1 modulation.
• Investigating CES1 levels in HCV-infected human-mouse chimeric livers.

Main Results:

• Carboxylesterase 1 (CES1) activity was significantly altered during HCV replication.
• CES1 knockdown reduced HCV replication, while CES1 upregulation enhanced it.
• CES1 facilitates HCV release, evidenced by decreased intracellular core protein and maintained high viral titers.
• CES1 activity promotes lipid droplet maturation, crucial for very low-density lipoprotein assembly and viral egress.
• Elevated endogenous CES1 levels were observed in HCV-infected chimeric mouse livers.

Conclusions:

• Carboxylesterase 1 (CES1) is a host factor that plays a critical role in facilitating Hepatitis C virus (HCV) propagation.
• CES1 influences HCV release, potentially by modulating lipid droplet metabolism and lipoprotein assembly.
• CES1 represents a potential therapeutic target for controlling HCV infection.