Characterization of SPP involved in pathogenesis of HCV

• Project/Area Number: 15H04736
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Virology
• Research Institution: Osaka University
• Principal Investigator: Matsuura Yoshiharu 大阪大学, 微生物病研究所, 教授 (50157252)
• Co-Investigator(Renkei-kenkyūsha): OKAMOTO Toru 大阪大学, 微生物病研究所, 准教授 (80628595) ; FUKUHARA Takasuke 大阪大学, 微生物病研究所, 准教授 (70598739)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2017: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: SPP / HCV

Outline of Final Research Achievements

We have previously reported that the maturation of core protein of hepatitis C virus (HCV) by the cleavage with signal peptide peptidase (SPP) is essential for propagation of HCV. In this study, we examined the inhibitory activity of inhibitors for γ-secretase, another intramembrane cleaving protease, to SPP and revealed that interaction of Val223 in SPP with dibenzoazepine structure in the γ-secretase inhibitors is critical for inhibition of SPP. Treatment with SPP suppressed maturation of HCV core proteins of all genotypes of HCV and did not induce emergence of drug-resistant viruses. These results suggest that SPP is an ideal target for the development of therapeutics against chronic hepatitis C.

Research Products

• [Journal Article] Characterization of recombinant Flaviviridae viruses possessing a small reporter-tag. (2018)
  • Author(s): Tamura T, Fukuhara T, Uchida T, Ono C, Mori H, Sato A, Fauzyah Y, Okamoto T, Kurosu T, Setoh YX, Imamura M, Tautz N6 Sakoda Y, Khromykh AA, Chayama K, Matsuura Y.
  • Journal Title: J Virol. Volume: 92 Issue: 2 Pages: 259-273
  • DOI: 10.1128/jvi.01582-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulation of Apoptosis during Flavivirus Infection. (2017)
  • Author(s): Okamoto T, Suzuki T, Kusakabe S, Tokunaga M, Hirano J, Miyata Y, Matsuura Y
  • Journal Title: Viruses Volume: 9 Issue: 9 Pages: 243-243
  • DOI: 10.3390/v9090243
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of SPP inhibitors suppressing propagation of HCV and protozoa (2017)
  • Author(s): Hirano J, Okamoto T, Sugiyama Y, Suzuki T, Kusakabe S, Tokunaga M, Fukuhara T, Sasai M, Tougan T, Matsunaga Y, Yamashita K, Sakai Y, Yamamoto M, Horii T, Standley DM, Moriishi K, Moriya K, Koike K, Matsuura Y.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114 Issue: 50
  • DOI: 10.1073/pnas.1712484114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of miR-122-independent propagation of HCV (2017)
  • Author(s): Ono C., Fukuhara T., Motooka D., Nakamura S., Okuzaki D., Yamamoto S., Tamura T., Mori H., Sato A., Uemura K., Fauzyah Y., Kurihara T., Suda T., Nishino A., Hmwe SS., Okamoto T., Tatsumi T., Takehara T., Chayama K., Wakita T., Koike K., Matsuura Y.
  • Journal Title: PLoS Pathogens Volume: 13
  • Peer Reviewed / Open Access
• [Journal Article] Host-derived apolipoproteins play comparable roles with viral secretory proteins Erns and NS1 in the infectious particle formation of Flaviviridae (2017)
  • Author(s): Takasuke Fukuhara, Tomokazu Tamura, Chikako Ono, Mai Shiokawa, Hiroyuki Mori, Kentaro Uemura, Satomi Yamamoto, Takeshi Kurihara, Toru Okamoto, Ryosuke Suzuki, Kentaro Yoshii, Takeshi Kurosu, Manabu Igarashi, Hiroshi Aoki, Yoshihiro Sakoda, Yoshiharu Matsuura
  • Journal Title: PLoS Pathogens Volume: 13
  • Peer Reviewed / Open Access
• [Journal Article] Quasispecies of Hepatitis C Virus Participate in Cell-Specific Infectivity. (2016)
  • Author(s): Fukuhara T, Yamamoto S, Ono C, Nakamura S, Motooka D, Mori H, Kurihara T, Sato A, Tamura T, Motomura T, Okamoto T, Imamura M, Ikegami T, Yoshizumi T, Soejima Y, Maehara Y, Chayama K, Matsuura Y.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 45228-45228
  • DOI: 10.1038/srep45228
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis. (2016)
  • Author(s): Aizawa S., Okamoto T., Sugiyama Y., Kouwaki T., Ito A., Suzuki T., Ono C., Fukuhara T., Yamamoto M., Okochi M., Hiraga N., Imamura M., Chayama K., Suzuki R., Shoji I., Moriishi K., Moriya K., Koike K., and Matsuura Y.
  • Journal Title: Nat. Commun. Volume: 7 Issue: 1 Pages: 1-12
  • DOI: 10.1038/ncomms11379
  • Peer Reviewed / Open Access
• [Journal Article] Arid5a regulates naive CD4+ T cell fate through selective stabilization of Stat3 mRNA (2016)
  • Author(s): Masuda, K., Ripley, B., Nyati, K., Dubey, P., Zaman, M., Hanieh, H., Hoga, M., Yamashita, K., Standley, D., Mashima, T., Katahira, M., Okamoto, T., Matsuura, Y., Takeuchi, O. and Kishimoto, T.
  • Journal Title: Journal of Experimental Medicine Volume: 213 Issue: 4 Pages: 605-619
  • DOI: 10.1084/jem.20151289
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory effect of CDK9 inhibitor FIT-039 on hepatitis B virus propagation (2016)
  • Author(s): T. Tanaka, K. Okuyama-Dobashi, S. Murakami, W. Chen, T. Okamoto, K. Ueda, T. Hosoya, Y. Matsuura, A. Ryo, Y. Tanaka, M. Hagiwara and K. Moriishi
  • Journal Title: Antiviral Research Volume: 133 Pages: 156164-156164
  • DOI: 10.1016/j.antiviral.2016.08.008
  • Peer Reviewed
• [Journal Article] 1TRC8-dependent degradation of hepatitis C virus immature core protein regulates viral propagation and pathogenesis. (2016)
  • Author(s): Aizawa S., Okamoto T., Sugiyama Y., Kouwaki T., Ito A., Suzuki T., Ono C., Fukuhara T., Yamamoto M., Okochi M., Hiraga N., Imamura M., Chayama K., Suzuki R., Shoji I., Moriishi K., Moriya K., Koike K., and Matsuura Y.
  • Journal Title: Nat. Commun. Volume: 未定
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Involvement of FKBP6 in hepatitis C virus replication (2015)
  • Author(s): Kasai H, Kawakami Y, Yokoe H, Yoshimura K, Matsuda M, Yasumoto J, Maekawa S, Yamashita A, Tanaka T, Ikeda M, Kato N, Okamoto T, Matsuura Y, Sakamoto N, Enomoto N, Takeda S, Fujii H, Tsubuki M, Kusunoki M, Moriishi K.
  • Journal Title: Scientific reports Volume: 5 Issue: 1 Pages: 16699-16699
  • DOI: 10.1038/srep16699
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Ｃ型肝炎ウイルスの増殖と病原性に関与する宿主因子 (2017)
  • Author(s): Yoshiharu Matsuura, Takasuke Fukuhara, Toru Okamoto
  • Organizer: 北大部局横断シンポジウム 第2回北大部局横断シンポジウム「免疫・癌・感染」
  • Place of Presentation: 北海道大学
  • Year and Date: 2017-03-14
• [Presentation] Ｃ型肝炎ウイルスの増殖と病原性に関与する宿主因子 (2017)
  • Author(s): 松浦善治、福原崇介、岡本 徹
  • Organizer: 北大部局横断シンポジウム 第2回北大部局横断シンポジウム「免疫・癌・感染」
  • Invited
• [Presentation] Viral secretory proteins Erns and NS1 play comparable roles with apolipoproteins in the infectious particle formation of Flaviviridae (2017)
  • Author(s): Takasuke Fukuhara, Tomokazu Tamura, Mai Shiokawa, Chikako Ono, Satomi Yamamoto, Hiroyuki Mori, Takeshi Kurihara, Asuka Sato, Kentaro Uemura, Toru Okamoto, Hiroshi Aoki, Yoshihiro Sakoda, Yoshiharu Matsuura
  • Organizer: The American Society for Virology (ASV) the 36th Annual Meeting
  • Int'l Joint Research
• [Presentation] Roles of miR-574-5p and miR-504-3p on the propagation of HCV in miR-122-deficient cells (2017)
  • Author(s): Chikako Ono, Takasuke Fukuhara, Tomokazu Tamura, Hiroyuki Mori, Asuka Sato, Yuzy Fauzyah, Toru Okamoto, Kazuhiko Koike, Yoshiharu Matsuura
  • Organizer: The American Society for Virology (ASV) the 36th Annual Meeting
  • Int'l Joint Research
• [Presentation] Characterization of Flaviviridae viruses possessing a reporter gene (2017)
  • Author(s): Tomokazu Tamura, Takasuke Fukuhara, Chikako Ono, Hiroyuki Mori, Takeshi Kurihara, Toru Okamoto, Takeshi Kurosu, Norbert Tautz, Yoshihiro Sakoda, Yoshiharu Matsuura
  • Organizer: The American Society for Virology (ASV) the 36th Annual Meeting
  • Int'l Joint Research
• [Presentation] Characterization of miR-122-independent propagation of HCV (2017)
  • Author(s): Chikako Ono, Takasuke Fukuhara, Tomokazu Tamura, Hiroyuki Mori, Asuka Sato, Yuzy Fauzyah, Toru Okamoto, Kazuaki Chayama, Kazuhiko Koike, Yoshiharu Matsuura
  • Organizer: 第16回あわじしま感染症・免疫フォーラム
  • Int'l Joint Research
• [Presentation] Characterization of recombinant Flaviviridae viruses possessing a small reporter-tag (2017)
  • Author(s): Tomokazu Tamura, Takasuke Fukuhara, Takuro Uchida, Chikako Ono, Hiroyuki Mori, Asuka Sato, Yuzy Fauzyah, Toru Okamoto, Takeshi Kurosu, Norbert Tautz, Yoshihiro Sakoda, Kazuaki Chayama, Yoshiharu Matsuura
  • Organizer: 第16回あわじしま感染症・免疫フォーラム
  • Int'l Joint Research
• [Presentation] Viral secretory glycoproteins of Pestivirus and Flavivirus have similar roles with exchangeable apolipoproteins on the formation of infectious HCV particles (2017)
  • Author(s): Takasuke Fukuhara, Tomokazu Tamura, Mai Shiokawa, Chikako Ono, Satomi Yamamoto Hiroyuki Mori, Asuka Sato, Shinya Yamada, Toru Okamoto, Hiroshi Aoki, Yoshihiro Sakoda, Yoshiharu Matsuura
  • Organizer: 24th International Symposium on Heepatitis C Virus and Related Viruses
  • Int'l Joint Research
• [Presentation] Engineering of Small Reporter-Tagged Flaviviridae Viruses Applicable to Antiviral Screening and in vivo Dynamics (2017)
  • Author(s): Tomokazu Tamura, Takasuke Fukuhara, Akatuski Saito, Takuro Uchida, Chikako Ono, Hiroyuki Mori, Toru Okamoto, Takeshi Kurosu, Norbert Tautz, Yoshihiro Sakoda, Tatuso Shioda, Kazuaki Chayama, Yoshiharu Matsuura
  • Organizer: 24th International Symposium on Heepatitis C Virus and Related Viruses
  • Int'l Joint Research
• [Presentation] Viral secretory glycoproteins Erns and NS1 play comparable roles with apolipoproteins in infectious particle formation of Flaviviridae (2017)
  • Author(s): Fukuhara Takasuke, Tamura Tomokazu, Matsuura Yoshiharu
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Involvement of other miRNA on the propagation of HCV in miR-1-deficient cells (2017)
  • Author(s): Chikako Ono, Takasuke Fukuhara, Tomokazu Tamura, Hiroyuki Mori, Asuka Sato, Yuzy Fauzyah, Toru Okamoto, Kazuaki Chayama, Kazuhiko Koike, Yoshiharu Matsuura
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Engineering of small reporter-tagged Flaviviridae viruses applicable to antiviral screening and in vivo dynamics (2017)
  • Author(s): Tomokazu Tamura, Takasuke Fukuhara, Takuro Uchida, Chikako Ono, Hiroyuki Mori, Asuka Sato, Yuzy Fauzyah, Toru Okamoto, Takeshi Kurosu, Norbert Tautz, Yoshihiro Sakoda, Kazuaki Chayama, Yoshiharu Matsuura
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Characterization of selective autophagy induced by HCV RNA replication (2017)
  • Author(s): Hiroyuki Mori, Takasuke Fukuhara, Chikako Ono, Tomokazu Tamura, Asuka Sato, Yuzy Fauzyah, Shinya Yamada, Toru Okamoto, Masami Wada, Takeshi Noda, Tamotsu Yoshimori, Yoshiharu Matsuura
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Signal peptide peptidase participates in propagation and pathogenesis of hepatitis C virus (2016)
  • Author(s): Yoshiharu Matsuura, Toru Okamoto
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2016-10-23
• [Presentation] Evaluation of γ-secretase inhibitors for HCV therapy (2016)
  • Author(s): Junki Hirano, Yukari Sugiyama, Tatsuya Suzuki, Shinji Kusakabe, Takasuke Fukuhara, Toru Okamoto, Yoshiharu Matsuura
  • Organizer: 23rd International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] Hepatitis C virus core protein interacts with Bnip3 and soppresses its dimerizatin and binding with LC3 (2016)
  • Author(s): Takeya Tsusumi,Akari Kado,Kazuya Okushin,Kenichiro Enooku,Hidetaka Fiujinaga,Kyoji Moriya,Hiroshi Yotsuyanagi,Yumi Kanegae,Izumu Sauto,Yoshiharu Mtsuura,Kazuhiko Koike
  • Organizer: 23rd International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] Single peptide peptidase a target for anti-HCV drug (2016)
  • Author(s): Toru Okamoto,Junki Hirano,Tatsuya Suzuki, ,Shinji Kusakabe,Takasuke Fukuhara Kohji Moriishi,Kazuhiko Koike and Yoshiharu Matsuura
  • Organizer: 23rd International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] TRC8-dependent proteasome degradation of immature core protein participates in pathogenesis of HCV (2015)
  • Author(s): Toru Okamoto, Yukari Sugiyama, Takahisa Kouwaki, Ayano Ito, Takasuke Fukuhara, Kohji Moriishi, Kazuhiko Koike, and Yoshiharu Matusuura
  • Organizer: The 22nd International Meeting on HCV and Related Viruses
  • Place of Presentation: Strasburg, France
  • Year and Date: 2015-10-08
  • Int'l Joint Research
• [Presentation] Signal peptide peptidase regulates propagation and pathogenesis of Hepatitis C Virus (2015)
  • Author(s): Toru Okamoto,Yukari Sugiyama,Ayano Ito, Takasuke Fukuhara, and Yoshiharu Matusuura
  • Organizer: 第14回あわじしま感染症免疫フォーラム
  • Place of Presentation: 淡路市、兵庫県
  • Year and Date: 2015-09-08
  • Int'l Joint Research
• [Presentation] Processing of core protein by signal peptide peptidase participates in propagation and pathogenesis of hepatitis C virus (2015)
  • Author(s): Toru Okamoto, Sayaka Aizawa, Yukari Sugiyama, Takahisa Kouwaki, Takasuke Fukuhara, Kohji Moriishi, Kazuhiko Koike, and Yoshiharu Matusuura
  • Organizer: The 34th Annual Meeting of the American Society for Virology
  • Place of Presentation: London, Canada
  • Year and Date: 2015-07-11
  • Int'l Joint Research
• [Remarks] 大阪大学微生物病研究所 分子ウイルス分野
  • URL: http://www-yoshi.biken.osaka-u.ac.jp