Significance of interaction between SPP and HCV core protein on viral life cycle.

• Project/Area Number: 19H03479
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Osaka University
• Principal Investigator: MATSUURA Yoshiharu 大阪大学, 微生物病研究所, 特任教授(常勤) (50157252)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: HCV / SPP / MHC / 慢性C型肝炎 / 蛋白質分解 / C型肝炎ウイルス / 小胞体品質管理機 / 小胞体品質機構

Outline of Research at the Start

C型肝炎ウイルス(HCV)に感染すると高率に慢性化し、インスリン抵抗性、脂肪肝、肝細胞癌を発症することが知られているが、その分子機構は不明な点が多い。我々はこれまでに、HCVのコア蛋白質の成熟に必須な宿主由来の Signal peptide peptidase (SPP)に注目し、SPPによって切断されて成熟したコア蛋白質が脂肪肝の発症に重要であること、SPPで切断されない未成熟なコア蛋白質は、小胞体の品質管理機構によって分解されることを明らかにしている。本研究は、SPPの活性を阻害した際に誘導される、新しい小胞体品質管理機構を培養細胞や遺伝子改変マウスを用いて詳細に解析する。

Outline of Final Research Achievements

Hepatitis C virus (HCV) evades host immune severance system to achieve chronic infection. In this study, we identified the mechanism of immune evasion of HCV by utilizing host signal peptide peptidase (SPP). SPP is crucial for production of MHC class I, which involves in elimination of viral infected cells. Inhibition of SPP induces HRD1 dependent degradation of MHC class I. Moreover, we identified core protein of HCV utilizes SPP during maturation and induces HRD1 dependent degradation of MHC class I.

Academic Significance and Societal Importance of the Research Achievements

C型肝炎ウイルス(HCV)は肝臓に感染すると高率に慢性化・持続感染し、慢性肝疾患の主要な原因となる。HCVが免疫を回避し、持続感染を行う分子メカニズムには解明されていない点が多く存在する。本研究では、HCVがSignal peptide peptidase (SPP)を利用して増殖する過程が、ウイルスによる免疫回避や持続感染に寄与していることを見出した。本研究成果により、HCVの免疫回避の分子機序の詳細や、免疫回避に関与する新規の宿主因子に関する知見が明らかとなった。

Research Products

• [Journal Article] Hepatitis C virus modulates signal peptide peptidase to alter host protein processing. (2021)
  • Author(s): 11.Hirano J, Yoshio S, Sakai Y, Songling L, Suzuki T, Itoh Y, Zhang H, Chen DV, Haga S, Oomori H, Kodama T, Maeda Y, Ono Y, Takahashi Y, Standley DM, Yamamoto M, Moriishi K, Moriya K, Kanto T, Takehara T, Koike K, Matsuura Y, Okamoto T.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 118(22) Issue: 22 Pages: 2026184118-2026184118
  • DOI: 10.1073/pnas.2026184118
  • Peer Reviewed / Open Access
• [Journal Article] Novel anti-flavivirus drugs targeting the nucleolar distribution of core protein (2020)
  • Author(s): Tokunaga Makoto、Miyamoto Yoichi、Suzuki Tatsuya、Otani Mayumi、Inuki Shinsuke、Esaki Tsuyoshi、Nagao Chioko、Mizuguchi Kenji、Ohno Hiroaki、Yoneda Yoshihiro、Okamoto Toru、Oka Masahiro、Matsuura Yoshiharu
  • Journal Title: Virology Volume: 541 Pages: 41-51
  • DOI: 10.1016/j.virol.2019.11.015
  • Peer Reviewed
• [Journal Article] In Vivo Dynamics of Reporter Flaviviridae Viruses. (2019)
  • Author(s): Tamura T, Igarashi M, Enkhbold B, Suzuki T, Okamatsu M, Ono C, Mori H, Izumi T, Sato A, Fauzyah Y, Okamoto T, Sakoda Y, Fukuhara T, Matsuura Y.
  • Journal Title: Journal of Virology Volume: 93 Issue: 22 Pages: 1-15
  • DOI: 10.1128/jvi.01191-19
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] USP15 Participates in Hepatitis C Virus Propagation through Regulation of Viral RNA Translation and Lipid Droplet Formation (2019)
  • Author(s): Kusakabe S、Suzuki T、Sugiyama Y、Haga S、Horike K、Tokunaga M、Hirano J、Zhang H、Chen DV、Ishiga H、Komoda Y、Ono C、Fukuhara T、Yamamoto M、Ikawa M、Satoh T、Akira S、Tanaka T、Moriishi Ki、Fukai M、Taketomi A、Yoshio S、Kanto T、Suzuki T、Okamoto T、Matsuura Y
  • Journal Title: Journal of Virology Volume: 93 Issue: 6 Pages: 1708-1718
  • DOI: 10.1128/jvi.01708-18
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of secretory glycoproteins in particle formation of Flaviviridae viruses. (2019)
  • Author(s): Fukuhara T, Matsuura Y.
  • Journal Title: Microbiology and Immunology Volume: 63 Issue: 10 Pages: 401-406
  • DOI: 10.1111/1348-0421.12733
  • NAID: 40022036966
  • Peer Reviewed
• [Presentation] ER stress sensor protein PERK participates in the degradation of immature HCV core protein. (2019)
  • Author(s): Junki Hirano, Toru Okamoto, Tatsuya Suzuki, Chikako Ono, Takasuke Fukuhara, and Yoshiharu Matsuura
  • Organizer: The 38th Annual Meeting of the American Society for Virology (Minnesota, USA).
  • Int'l Joint Research
• [Presentation] TLR ligands stimulate in vivo pathogenicity of Japanese encephalitis virus (2019)
  • Author(s): Tatsuya Suzuki1, Toru Okamoto1, Yuka Miyata1, Chikako Ono1, Takasuke Fukuhara1, Akatsuki Saito2, Yasuko Orba3, Yuki Eshita3, Hirofumi Sawa3, and Yoshiharu Matsuura1
  • Organizer: The 38th Annual Meeting of the American Society for Virology (Minnesota, USA).
  • Int'l Joint Research
• [Presentation] Involvement of various miRNAs for an efficient replication of HCV (2019)
  • Author(s): Chikako Ono, Takasuke Fukuhara, Tomokazu Tamura, Hiroyuki Mori, Asuka Sato, Takuma Izumi, Yuzy Fauzyah, Toru Okamoto, and Yoshiharu Matsuura
  • Organizer: The 38th Annual Meeting of the American Society for Virology (Minnesota, USA).
  • Int'l Joint Research
• [Presentation] Flavivirus NS1 protein plays a crucial role in the infectious particle formation (2019)
  • Author(s): Takasuke Fukuhara, Tomokazu Tamura, Shiho Torii, Chikako Ono, Kentaro Kajiwara, Yuhei Morioka, Takuya Yamamoto, Yuzy Fauzyah, Takuma Izumi, Yoshihiro Sakoda, Yoshiharu Matsuura
  • Organizer: The 18th Awaji International Forum on Infection and Immunity
  • Int'l Joint Research
• [Presentation] Involvement of various miRNAs for an efficient replication of HCV (2019)
  • Author(s): Chikako Ono, Takasuke Fukuhara, Tomokazu Tamura, Hiroyuki Mori, Asuka Sato, Takuma Izumi, Yuzy Fauzyah, Toru Okamoto, and Yoshiharu Matsuura
  • Organizer: The 18th Awaji International Forum on Infection and Immunity
  • Int'l Joint Research
• [Presentation] Characterization of mutation in the 5’UTR of HCV in miR-122-dependent propagation (2019)
  • Author(s): Chikako Ono, Takasuke Fukuhara, Yuzy Fauzyah, Shiho Torii, Asuka Sato, Takuma Izumi, Takuya Yamamoto, Yuhei Morioka, and Yoshiharu Matsuura
  • Organizer: 第67回日本ウイルス学会
• [Presentation] Flavivirus NS1 protein plays a crucial role in the infectious particle formation (2019)
  • Author(s): Takasuke Fukuhara, Tomokazu Tamura, Shiho Torii, Chikako Ono, Kentaro Kajiwara, Yuhei Morioka, Takuya Yamamoto, Yuzy Fauzyah, Takuma Izumi, Yoshihiro Sakoda, Yoshiharu Matsuura
  • Organizer: 第67回日本ウイルス学会
• [Presentation] Ｃ型肝炎対策の残された課題 (2019)
  • Author(s): 松浦善治
  • Organizer: 第23回日本ワクチン学会学術集会
  • Invited