Proteomic Analysis of Hepatitis C Virus (HCV) Core Protein Transfection and Host Regulator PA28γ Knockout in HCV Pathogenesis: A Network-Based Study

Hepatitis C virus (HCV) causes chronic liver disease
worldwide. HCV Core protein (Core) forms the viral capsid and is crucial
for HCV pathogenesis and HCV-induced hepatocellular carcinoma, through
its interaction with the host factor proteasome activator PA28γ.
Here, using BD-PowerBlot high-throughput Western array, we attempt
to further investigate HCV pathogenesis by comparing the protein levels
in liver samples from Core-transgenic mice with or without the knockout
of PA28γ expression (abbreviated PA28γ–/–CoreTG and CoreTG, respectively) against the wild-type (WT). The
differentially expressed proteins integrated into the human interactome
were shown to participate in compact and well-connected cellular networks.
Functional analysis of the interaction networks using a newly developed
data warehouse system highlighted cellular pathways associated with
vesicular transport, immune system, cellular adhesion, and cell growth
and death among others that were prominently influenced by Core and
PA28γ in HCV infection. Follow-up assays with in vitro HCV cell culture systems validated VTI1A, a vesicular transport
associated factor, which was upregulated in CoreTG but not in PA28γ–/–CoreTG, as a novel regulator of HCV release
but not replication. Our analysis provided novel insights into the
Core-PA28γ interplay in HCV pathogenesis and identified potential
targets for better anti-HCV therapy and potentially novel biomarkers
of HCV infection.