Understanding the biological context of NS5A-host interactions in HCV infection: a network-based approach

J Proteome Res. 2013 Jun 7;12(6):2537-51. doi: 10.1021/pr3011217. Epub 2013 May 17.

Abstract

Hepatitis C virus (HCV) is a major cause of chronic liver disease. HCV NS5A 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 NS5A and host factors in HCV pathogenesis, we generated an extensive physical interaction map between NS5A and cellular factors. By combining a yeast two-hybrid assay with comprehensive literature mining, we built the NS5A interactome composed of 132 human proteins that interact with NS5A. 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 NS5A with the components of the host cellular networks. The NS5A-host interactions that were integrated with the HPI were shown to participate in compact and well-connected cellular networks. Functional analysis of the NS5A "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 NS5A-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 NS5A protein in HCV pathogenesis and provides potential targets for more effective anti-HCV therapeutic intervention.

MeSH terms

  • Carrier Proteins / genetics*
  • Carrier Proteins / immunology
  • Cell Adhesion
  • Cell Line
  • Data Mining
  • Gene Expression
  • Hepacivirus / immunology*
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / immunology
  • Hepatitis C, Chronic / virology
  • Hepatocytes / immunology
  • Hepatocytes / virology
  • Host-Pathogen Interactions*
  • Humans
  • Membrane Proteins / genetics*
  • Membrane Proteins / immunology
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / immunology
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Interaction Maps*
  • Signal Transduction
  • Two-Hybrid System Techniques
  • Viral Nonstructural Proteins / genetics*
  • Viral Nonstructural Proteins / immunology

Substances

  • Carrier Proteins
  • Membrane Proteins
  • NS-5 protein, hepatitis C virus
  • Nerve Tissue Proteins
  • RTN1 protein, human
  • RTN3 protein, human
  • Viral Nonstructural Proteins