The role of ubiquitin-proteasome system in hepatitis B virus replication

• Project/Area Number: 18K07961
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: TANAKA YASUO 東京大学, 医学部附属病院, 助教 (40422290)
• Co-Investigator(Kenkyū-buntansha): 建石 良介 東京大学, 医学部附属病院, 講師 (50444089)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: HBV / HBV Xタンパク / ユビキチン・プロテアソーム系 / ユビキチンリガーゼ / CUL4-DDB1 / Xタンパク

Outline of Final Research Achievements

In this study, we investigated the role of ubiquitin-proteasome system in HBV replication. We identified DDX1(ATP-dependent RNA helicase DDX1) as a novel HBx-interacting protein using a tandem affinity purification method and demonstrated that DDX1 enhanced HBV RNA transcription. Furthermore, the ATPase domain of DDX1 was responsible for the enhancement of HBV replication. These results suggest that DDX1 could be an attractive therapeutic target for inhibiting HBV pathogenesis.

Academic Significance and Societal Importance of the Research Achievements

B型肝炎ウイルスは既存の内服薬により増殖を抑えることが可能だが、長期投与による薬剤耐性株の出現と薬剤中止による肝炎再燃が大きな問題となっており、新規抗ウイルス薬の開発が求められている。本研究ではタンパク分解系であるユビキチン・プロテアソーム系のB型肝炎ウイルス複製における役割を検討することにより、ウイルスの増殖に関与する宿主タンパクを同定し得た。本研究の新規治療法の開発への寄与が期待される。

Research Products

• [Journal Article] Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis (2021)
  • Author(s): Takuma Nakatsuka, Keisuke Tateishi*, Hiroyuki Kato, Hiroaki Fujiwara, Keisuke Yamamoto, Yotaro Kudo, Hayato Nakagawa, Yasuo Tanaka, Hideaki Ijichi, Tsuneo Ikenoue, Takeaki Ishizawa, Kiyoshi Hasegawa, Makoto Tachibana, Yoichi Shinkai, Kazuhiko Koike
  • Journal Title: Cell Death and Disease Volume: 12 Issue: 1 Pages: 99111-99111
  • DOI: 10.1038/s41419-020-03381-1
  • Peer Reviewed / Open Access
• [Journal Article] Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer (2020)
  • Author(s): Takahashi Ryota、Ijichi Hideaki、Sano Makoto、Miyabayashi Koji、Mohri Dai、Kim Jinsuk、Kimura Gen、Nakatsuka Takuma、Fujiwara Hiroaki、Yamamoto Keisuke、Kudo Yotaro、Tanaka Yasuo、Tateishi Keisuke、Nakai Yousuke、Morishita Yasuyuki、Soma Katsura、Takeda Norihiko、Moses Harold L.、Isayama Hiroyuki、Koike Kazuhiko
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41598-020-78320-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of Histone Methyltransferase G9a Suppresses Mutant Kras-driven Pancreatic Carcinogenesis Carcinogenesis (2020)
  • Author(s): Hiroyuki Kato, Keisuke Tateishi*, Hiroaki Fujiwara, Hideaki Ijichi, Keisuke Yamamoto, Takuma Nakatsuka, Miwako Kakiuchi, Makoto Sano, Yotaro Kudo, Yoku Hayakawa, Hayato Nakagawa, Yasuo Tanaka, Motoyuki Otsuka, Yoshihiro Hirata, Makoto Tachibana, Yoichi Shinkai, Kazuhiko Koike
  • Journal Title: Cancer Genomics Proteomics Volume: 17 Issue: 6 Pages: 695705-695705
  • DOI: 10.21873/cgp.20224
  • Peer Reviewed / Open Access
• [Journal Article] Improved liver function in patients with cirrhosis due to chronic hepatitis C virus who achieve sustained virologic response is not accompanied by increased liver volume (2020)
  • Author(s): Wake Taijiro、Tateishi Ryosuke、Fukumoto Tsuyoshi、Nakagomi Ryo、Kinoshita Mizuki Nishibatake、Nakatsuka Takuma、Sato Masaya、Minami Tatsuya、Uchino Koji、Enooku Kenichiro、Nakagawa Hayato、Fujinaga Hidetaka、Asaoka Yoshinari、Tanaka Yasuo、Otsuka Motoyuki、Koike Kazuhiko
  • Journal Title: PLOS ONE Volume: 15 Issue: 4 Pages: e0231836-e0231836
  • DOI: 10.1371/journal.pone.0231836
  • Peer Reviewed / Open Access
• [Journal Article] Mutant IDH1 confers resistance to energy stress in normal biliary cells through PFKP-induced aerobic glycolysis and AMPK activation (2019)
  • Author(s): Fujiwara H、Tateishi K、Misumi K、Hayashi A、Igarashi K、Kato H、Nakatsuka T、Suzuki N、Yamamoto K、Kudo Y、Hayakawa Y、Nakagawa 、Tanaka Y、Ijichi H、Kogure H、Nakai Y、Isayama H、Hasegawa K、Fukayama M、Soga T、Koike K
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 18859-18859
  • DOI: 10.1038/s41598-019-55211-w
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Non-invasive Method for Predicting Liver Fibrosis by Quantifying the Hepatic Vein Waveform. (2019)
  • Author(s): Soroida Y, Nakatsuka T, Sato M, Nakagawa H, Tanaka M, Yamauchi N, Wake T, Nakagomi R, Kinoshita MN, Minami T, Uchino K, Enooku K, Asaoka Y, Tanaka Y, Endo M, Nakamura A, Kobayashi T, Kurihara M, Hikita H, Sato M, Gotoh H, Iwai T, Fukayama M, Ikeda H, Tateishi R, Yatomi Y, Koike K.
  • Journal Title: Ultrasound Med Biol. Volume: 45 Issue: 9 Pages: 2363-2371
  • DOI: 10.1016/j.ultrasmedbio.2019.05.028
  • Peer Reviewed
• [Journal Article] Successful treatment of chronic hepatitis C virus infection with crushed glecaprevir/pibrentasvir administered via a percutaneous endoscopic gastrostomy tube: case report and review of the literature. (2019)
  • Author(s): Tanaka Y、Tateishi R、Koike K
  • Journal Title: Clinical Journal of Gastroenterology Volume: 12 Issue: 6 Pages: 588-591
  • DOI: 10.1007/s12328-019-00997-5
  • Peer Reviewed
• [Journal Article] Ischemic complications after percutaneous radiofrequency ablation of liver tumors: Liver volume loss and recovery (2019)
  • Author(s): Wake T、Tateishi R、Nakagomi R、Fujiwara N、Kinoshita MN、Nakatsuka T、Sato M、Minami T、Uchino K、Enooku K、Nakagawa H、Asaoka Y、Tanaka Y、Shiina S、Koike K
  • Journal Title: Hepatology Research Volume: 49 Issue: 4 Pages: 453-461
  • DOI: 10.1111/hepr.13302
  • Peer Reviewed
• [Journal Article] Blocking CXCLs?CXCR2 axis in tumor?stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment (2019)
  • Author(s): Sano Makoto、Ijichi Hideaki、Takahashi Ryota、Miyabayashi Koji、Fujiwara Hiroaki、Yamada Tomoharu、Kato Hiroyuki、Nakatsuka Takuma、Tanaka Yasuo、Tateishi Keisuke、Morishita Yasuyuki、Moses Harold L.、Isayama Hiroyuki、Koike Kazuhiko
  • Journal Title: Oncogenesis Volume: 8 Issue: 2 Pages: 8-8
  • DOI: 10.1038/s41389-018-0117-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Proteoglycans Are Attractive Biomarkers and Therapeutic Targets in Hepatocellular Carcinoma. (2018)
  • Author(s): Tanaka Y, Tateishi R, Koike K.
  • Journal Title: Int J Mol Sci. Volume: 19 Issue: 10 Pages: 3070-3070
  • DOI: 10.3390/ijms19103070
  • Peer Reviewed / Open Access
• [Journal Article] Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1 (2018)
  • Author(s): Fujiwara Hiroaki、Tateishi Keisuke、Kato Hiroyuki、Nakatsuka Takuma、Yamamoto Keisuke、Tanaka Yasuo、Ijichi Hideaki、Takahara Naminatsu、Mizuno Suguru、Kogure Hirofumi、Matsubara Saburo、Nakai Yousuke、Koike Kazuhiko
  • Journal Title: Cancer Science Volume: 109 Issue: 11 Pages: 3602-3610
  • DOI: 10.1111/cas.13784
  • Peer Reviewed
• [Journal Article] CPT2 downregulation adapts HCC to lipid-rich environment and promotes carcinogenesis via acylcarnitine accumulation in obesity (2018)
  • Author(s): Fujiwara Naoto、Nakagawa Hayato、Enooku Kenichiro、Otsuka Motoyuki、Tateishi Keisuke、Koike Kazuhiko
  • Journal Title: Gut Volume: 67 Issue: 8 Pages: 1493-1504
  • DOI: 10.1136/gutjnl-2017-315193
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 治療後 cell-free DNA 解析による分子標的薬の治療効果予測 (2020)
  • Author(s): 中塚拓馬、中川勇人、早田有希、和気泰次郎、山田友春、木下瑞希、中込良、 佐藤雅哉、南達也、榎奥健一郎、工藤洋太郎、田中康雄、 大塚基之、建石良介、小池和彦
  • Organizer: 第23回日本肝がん分子標的治療研究会
• [Presentation] 肝癌前駆細胞を制御するヒストンメチル化修飾機構 (2018)
  • Author(s): 中塚拓馬，立石敬介，工藤洋太郎，山本恵介，中川勇人，藤原弘明，田中康雄，酒井寿郎，油谷浩幸，眞貝洋一，小池和彦.
  • Organizer: 第25 回肝細胞研究会
• [Presentation] 肝癌前駆細胞を制御するヒストンメチル化修飾機構 (2018)
  • Author(s): 中塚拓馬，立石敬介，工藤洋太郎，山本恵介，中川勇人，藤原弘明，田中康雄，酒井寿郎，油谷浩幸，眞貝洋一，小池和彦.
  • Organizer: 第55 回日本臨床分子医学会学術集会
• [Presentation] ATP 依存性RNA ヘリカーゼDDX1 のHBV 複製における役割の検討 (2018)
  • Author(s): 田中康雄，立石敬介，小池和彦.
  • Organizer: 第104 回日本消化器病学会総会