Research

Molecular mechanisms of HCV propagation and pathogenesis

The Project Leader's Profile

Yoshiharu Matsuura

Professor, Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University

In 1980, graduated from the Graduate School of Veterinary Medicine, Hokkaido University. After working at Daiichi Seiyaku Co., Ltd, as a researcher, he appointed as Research Associate of the National Institute of Health in 1982 and promoted to Section Chief of the Laboratory of Hepatitis Virus in 1992. In 1984, he appointed as Research Fellow at NERC Institute of Virology, Oxford University, UK for two years. Since 2000, he holds the current position. Specialized in virology, especially in hepatitis C virus and viral vectors. He has received Tagaya Isamu Memorial Award for Vaccine Research and Sugiura Memorial Incentive Award for Young Virologist.

Project Leader
  • Yoshiharu Matsuura, DVM, PhD, Professor, Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University
Research Members
  • Kohji Moriishi, DVM, PhD, Associate professor, Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University
  • Yoshio Mori, DVM, PhD, Assistant professor, Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University
  • Hideki Tani, PhD, Assistant professor, Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University
Research Collaborators
  • Takayuki Abe, PhD, Research associate, Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University
  • Shuhei Taguwa, PhD, Research associate, Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University

Summary

We are working for the understanding of the molecular mechanisms of entry, replication, immune escape, and pathogenesis of hepatitis C virus (HCV). The major obstacles of HCV research are the lack of robust cell culture systems to support replication of authentic HCV from patient's sera and small animal models exhibiting susceptibility to HCV. HCV infection induces chronic hepatitis with steatosis and cirrhosis, and eventually leads to hepatocellular carcinoma (HCC). It was reported that hepatic steatosis and HCC were induced in transgenic mice expressing the HCV core protein, suggesting that the HCV core protein plays a pivotal role in the development of HCC. We have shown that HCV core protein specifically binds to the proteasome activator PA28γ in the nucleus and is degraded via a PA28γ-dependent pathway and that a knockout of the PA28γ gene in the HCV transgenic mice induces an accumulation of HCV core protein in the nucleus of hepatocytes and inhibits the development of liver steatosis and HCC. These findings suggest that some fraction of the HCV core protein migrates into the nucleus of hepatocytes and is degraded via a PA28γ-dependent pathway in vivo, and that PA28γ plays a crucial role in the development of liver steatosis and HCC induced by HCV core protein. We also indicated that PA28γ is required for the expression of SREBP-1c by HCV core protein. Furthermore, we demonstrated that co-chaperons, FK506-binding proteins 8 and human Bind-1, recruit Hsp90 to the replication complex of HCV through the interaction with NS5A protein and play crucial roles on the replication of HCV genome. In this project, we would like to clarify the molecular mechanisms of replication and pathogenesis of HCV through the viewpoint of host cellular organelle network.


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Some of Recent Papers

  1. Okamoto T., Omori H., Kaname Y., Abe T., Nishimura Y., Suzuki T., Miyamura T., Yoshimori T., Moriishi K., and Matsuura Y. A single amino acid mutation in hepatitis C virus NS5A disrupting FKBP8 interaction impairs viral replication. J. Virol., 82, 3480-3489, 2008.
  2. Taguwa S., Okamoto T., Abe T., Mori Y., Suzuki T., Moriishi K., and Matsuura Y. Human butyrate-induced transcript 1 interacts with hepatitis C virus NS5A and regulates viral replication. J. Virol., 82, 2631-2641, 2008.
  3. Moriishi K., Mochizuki R., Moriya K., Miyamoto H., Mori Y., Abe T., Murata S., Tanaka K., Miyamura T., Suzuki T., Koike K., and Matsuura Y. Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. PNAS 104, 1661-1666, 2007.
  4. Abe T., Kaname Y., Hamamoto I., Tsuda Y., Wen X., Taguwa S., Moriishi K., Takeuchi O., Kawai T., Kanto T., Hayashi N., Akira S., and Matsuura Y. Hepatitis C virus nonstructural protein 5A modulates TLR-MyD88-dependent signaling pathway in the macrophage cell lines. J. Virol. 81, 8953-8966, 2007.
  5. Okamoto T. Nishimura Y., Ichimura T., Suzuki K., Miyamura T., Suzuki T., Moriishi K., and Matsuura Y. Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90. EMBO J., 25, 5015-5025, 2006