Understanding the Biological Context of NS5A-Host Interactions in HCV Infection: A Network-Based Approach

作者：Tripathi Lokesh P; Kambara Hiroto; Chen Yi An; Nishimura Yorihiro; Moriishi Kohji; Okamoto Toru; Morita Eiji; Abe Takayuki; Mori Yoshio; Matsuura Yoshiharu; Mizuguchi Kenji^*

来源：Journal of Proteome Research, 2013, 12(6): 2537-2551.

DOI：10.1021/pr3011217

• HCV
• NSSA
• host-pathogen protein-protein interactions
• biological network analysis
• literature mining
• pathway enrichment analysis
• siRNA knockdown
• target discovery
• TargetMine
• yeast two-hybrid

Hepatitis C virus (HCV) is a major cause of chronic liver disease. HCV NSSA protein plays an important role in HCV infection through its interactions with other HCV proteins and host factors. In an attempt to further our understanding of the biological context of protein interactions between NSSA and host factors in HCV pathogenesis, we generated an extensive physical interaction map between NSSA and cellular factors. By combining a yeast two-hybrid assay with comprehensive literature mining, we built the NSSA interactome composed of 132 human proteins that interact with NSSA These interactions were integrated into a high-confidence human protein interactome (HPI) with the help of the TargetMine data warehouse system to infer an overall protein interaction map linking NSSA with the components of the host cellular networks. The NSSA-host interactions that were integrated with the HPI were shown to participate in compact and well-connected cellular networks. Functional analysis of the NSSA "infection" network using TargetMine highlighted cellular pathways associated with immune system, cellular signaling, cell adhesion, cellular growth and death among others, which were significantly targeted by NSSA host interactions. In addition, cellular assays with in vitro HCV cell culture systems identified two ER-localized host proteins RTN1 and RTN3 as novel regulators of HCV propagation. Our analysis builds upon the present understanding of the role of NSSA protein in HCV pathogenesis and provides potential targets for more effective anti-HCV therapeutic intervention.

• 出版日期2013-6