Analysis of the effect of Nrf2-Prdx1 pathway on the degradation of hepatitis B virus RNA

• Project/Area Number: 21K07040
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Kobe University
• Principal Investigator: デン リン 神戸大学, 医学研究科, 助教 (40437497)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HBV / HBV RNA 分解 / Nrf2 / 抗酸化応答 / Prdx1 / HBV RNA分解 / B型肝炎ウイルス / HBx

Outline of Research at the Start

B型肝炎ウイルス(HBV)は、ヒト肝細胞に感染し、慢性肝炎、肝硬変、肝細胞癌などを含む肝疾患を引き起こすが、現時点において、根本的な治療法は確立されておらず、HBVを体内から完全に排除することは不可能とされている。
最近我々は、HBVのXタンパク質 (HBx)の新規宿主結合因子として抗酸化酵素Peroxiredoxin 1 (Prdx1) を見出し、Prdx1がHBxに結合することにより、HBV RNA を分解へと導くことを報告した。従って、本研究では、申請者が世界に先駆けて見出した、「Prdx1を介したHBV RNAの新規分解機構」のより詳細なメカニズムを明らかにすることにより、HBV関連疾患に対する新たな治療戦略シーズへの可能性を提示することを目的とする。

Outline of Annual Research Achievements

B型肝炎ウイルス(HBV)は、ヒト肝細胞に感染し、慢性肝炎、肝硬変、肝細胞癌などを含む肝疾患を引き起こすが、現時点において、HBVを体内から完全に排除することは不可能とされている。本研究では、HBV RNAの新規分解機構の詳細なメカニズムを明らかにすることにより、HBV関連疾患に対する新たな治療戦略の可能性を提示することを目的としている。
申請者は以前、転写因子Nrf2の過剰発現がHBV増殖を有意に抑制することを見出した。そこで、令和5年度は、HBV感染によるNrf2経路の活性化、また、Nrf2によるHBVの増殖抑制機構について詳細に検討し、以下の成果を得た。(1) HBV感染およびHBxタンパク質の発現はNrf2タンパク質の安定化と活性化を亢進させることを明らかにした。(2) HBxが酸化ストレスセンサーであるKeap1のdouble-glycine repeat (DGR)ドメインを介してKeap1と相互作用することにより、Keap1-Nrf2相互作用を阻害することを明らかにした。(3) Nrf2はHBV core promoterに結合し、core promoter活性を阻害することにより、HBV複製を抑制することを明らかにした。(4) HBxがNrf2のK6型ポリユビキチン化を誘導することを見出し、さらに、HECT型E3ユビキチンリガーゼHUWE1がNrf2のK6型ポリユビキチン化に関与していることを明らかにした。以上のことから、HBV感染細胞において、Keap1はHBxと相互作用することにより、Nrf2の活性化を誘導し、活性化したNrf2がHBV core promoter活性を阻害することがNrf2によるHBVの増殖抑制メカニズムの一つであると考えられた。
これらの成果は、本研究の目的達成に向けた重要な知見であると考える。

Research Products

• [Int'l Joint Research] Faculty of Medicine/Public Health and Nursing/Universitas Gadjah Mada(インドネシア)
• [Int'l Joint Research] Institute of Tropical Disease/Universitas Airlangga(インドネシア)
• [Int'l Joint Research] Department of Clinical Microbiology/Faculty of Medicine/Universitas Udayana(インドネシア)
• [Int'l Joint Research] Department of Medical Microbiology/School of Medicine/Universitas Airlangga(インドネシア)
• [Int'l Joint Research] Department of Biochemistry/School of Medicine/Universitas Airlangga(インドネシア)
• [Journal Article] Oxidative stress sensor Keap1 recognizes HBx protein to activate the Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication (2023)
  • Author(s): Ariffianto Adi、Deng Lin、Abe Takayuki、Matsui Chieko、Ito Masahiko、Ryo Akihide、Aly Hussein Hassan、Watashi Koichi、Suzuki Tetsuro、Mizokami Masashi、Matsuura Yoshiharu、Shoji Ikuo
  • Journal Title: Journal of Virology Volume: 97 Issue: 10 Pages: 1-35
  • DOI: 10.1128/jvi.01287-23
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatitis C Virus Disrupts Annexin 5-Mediated Occludin Integrity through Downregulation of Protein Kinase Cα (PKCα) and PKCη Expression, Thereby Promoting Viral Propagation (2023)
  • Author(s): Abe Takayuki、Marutani Yuki、Deng Lin、Matsui Chieko、Fukasawa Masayoshi、Suzuki Ryosuke、Wakita Takaji、Matsuura Yoshiharu、Shoji Ikuo
  • Journal Title: Journal of Virology Volume: 97 Issue: 6
  • DOI: 10.1128/jvi.00655-23
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A household survey of intrafamily norovirus transmission (2023)
  • Author(s): Juniastuti、Utsumi Takako、Yamani Laura Navika、Dinana Zayyin、Gunawan Emily、Maharani Aussie Tahta、Fitria Anisa Lailatul、Wahyuni Rury M.、Soetjipto、Doan Yen Hai、Shimizu Hiroyuki、Ishii Koji、Matsui Chieko、Deng Lin、Abe Takayuki、Katayama Kazuhiko、Lusida Maria Inge、Shoji Ikuo
  • Journal Title: Journal of Medical Virology Volume: 95 Issue: 10
  • DOI: 10.1002/jmv.29164
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Complete genome analyses of G12P[8] rotavirus strains from hospitalized children in Surabaya, Indonesia, 2017-2018 (2023)
  • Author(s): Laura Navika Yamani, Takako Utsumi, Yen Hai Doan, Yoshiki Fujii, Zayyin Dinana, Rury Mega Wahyuni, Emily Gunawan, Soegeng Soegijanto, Alpha Fardah Athiyyah, Subijanto Marto Sudarmo, Reza Gunadi Ranuh, Andy Darma, Soetjipto, Juniastuti, Rheza Gandi Bawono, Chieko Matsui, Lin Deng, etc.
  • Journal Title: Journal of Medical Virology Volume: 95 Issue: 2
  • DOI: 10.1002/jmv.28485
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcription Factor JunB Suppresses Hepatitis C Virus Replication (2023)
  • Author(s): Adi Ariffianto, Lin Deng, Saki Harada, Yujiao Liang, Chieko Matsui, Takayuki Abe, Ikuo Shoji
  • Journal Title: Kobe Journal of Medical Sciences Volume: 69
  • Peer Reviewed
• [Journal Article] Cellular Release of Infectious Hepatitis C Virus Particles via Endosomal Pathways (2023)
  • Author(s): Deng Lin、Solichin Muchamad Ridotu、Adyaksa Dewa Nyoman Murti、Septianastiti Maria Alethea、Fitri Rhamadianti Aulia、Suwardan Gede Ngurah Rsi、Matsui Chieko、Abe Takayuki、Shoji Ikuo
  • Journal Title: Viruses Volume: 15 Issue: 12 Pages: 2430-2430
  • DOI: 10.3390/v15122430
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatitis C Virus-Induced ROS/JNK Signaling Pathway Activates the E3 Ubiquitin Ligase Itch to Promote the Release of HCV Particles via Polyubiquitylation of VPS4A (2022)
  • Author(s): Deng Lin、Liang Yujiao、Ariffianto Adi、Matsui Chieko、Abe Takayuki、Muramatsu Masamichi、Wakita Takaji、Maki Masatoshi、Shibata Hideki、Shoji Ikuo
  • Journal Title: Journal of Virology Volume: 96 Issue: 6 Pages: 1811-21
  • DOI: 10.1128/jvi.01811-21
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatitis C virus NS5A protein promotes the lysosomal degradation of diacylglycerol O-acyltransferase 1 (DGAT1) via endosomal microautophagy (2022)
  • Author(s): Putu Yuliandari, Chieko Matsui, Lin Deng, Takayuki Abe, Hiroyuki Mori, Shuhei Taguwa, Chikako Ono, Takasuke Fukuhara, Yoshiharu Matsuura, Ikuo Shoji
  • Journal Title: Autophagy Reports Volume: 1 Issue: 1 Pages: 264-285
  • DOI: 10.1080/27694127.2022.2095591
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Role of Chaperone-Mediated Autophagy in Hepatitis C Virus-Induced Pathogenesis (2021)
  • Author(s): Matsui Chieko、Yuliandari Putu、Deng Lin、Abe Takayuki、Shoji Ikuo
  • Journal Title: Frontiers in Cellular and Infection Microbiology Volume: 11 Pages: 1-8
  • DOI: 10.3389/fcimb.2021.796664
  • NAID: 120007184287
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HERC5 E3 ligase mediates ISGylation of hepatitis B virus X protein to promote viral replication (2021)
  • Author(s): Bawono Rheza Gandi、Abe Takayuki、Qu Mengting、Kuroki Daisuke、Deng Lin、Matsui Chieko、Ryo Akihide、Suzuki Tetsuro、Matsuura Yoshiharu、Sugiyama Masaya、Mizokami Masashi、Shimotohno Kunitada、Shoji Ikuo
  • Journal Title: Journal of General Virology Volume: 102 Issue: 10
  • DOI: 10.1099/jgv.0.001668
  • Peer Reviewed / Open Access
• [Journal Article] Molecular epidemiology and genetic diversity of norovirus infection in children hospitalized with acute gastroenteritis in East Java, Indonesia in 2015?2019 (2021)
  • Author(s): Utsumi Takako、Lusida Maria Inge、Dinana Zayyin、Wahyuni Rury Mega、Soegijanto Soegeng、Soetjipto、Athiyyah Alpha Fardah、Sudarmo Subijanto Marto、Ranuh Reza Gunadi、Darma Andy、Juniastuti、Ishii Koji、Shoji Ikuo et al.
  • Journal Title: Infection, Genetics and Evolution Volume: 88 Pages: 104703-104703
  • DOI: 10.1016/j.meegid.2020.104703
  • NAID: 120006993632
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NS5A-ISGylation via Lysine 26 Has a Critical Role for Efficient Propagation of Hepatitis C Virus Genotype 2a (2021)
  • Author(s): Bawono Rheza Gandi, Abe Takayuki, Shibata Yasuaki, Matsui Chieko, Deng Lin, Shoji Ikuo.
  • Journal Title: Kobe Journal of Medical Sciences Volume: 67
  • NAID: 120007169870
  • Peer Reviewed / Open Access
• [Presentation] 1.Oxidative stress sensor Keap1 recognizes HBx protein to activate Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication. (2023)
  • Author(s): Deng L, Ariffianto A, Matsui C, Abe T, Ito M, Suzuki T, Matsuura Y, Shoji I.
  • Organizer: The 9th Japan-Taiwan-Korea HBV Research Symposium
  • Int'l Joint Research
• [Presentation] 2.HERC5 E3 ligase mediates ISGylation of hepatitis B virus X protein (HBx) to promote viral replication. (2023)
  • Author(s): Abe T, Bawono RG, Qu M, Kuroki D, Deng L, Matsui C, Ryo A, Suzuki T, Matsuura Y, Sugiyama M, Mizokami M, Shimotohno K, Shoji I.
  • Organizer: The 9th Japan-Taiwan-Korea HBV Research Symposium
  • Int'l Joint Research
• [Presentation] Oxidative stress sensor Keap1 recognizes HBx protein to activate the Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication (2023)
  • Author(s): Deng L, Ariffianto A, Abe T, Matsui C, Ito M, Ryo A, Aly HH, Watashi K, Suzuki T, Mizokami M, Matsuura Y, Shoji I.
  • Organizer: 2023 International HBV Meeting
  • Int'l Joint Research
• [Presentation] A novel bile acid derivative inhibits Hepatitis B Virus infection by disrupting internalization of NTCP and PreS1 complexes at the entry step. (2023)
  • Author(s): Suwardana GR, Abe T, Kuroki D, Deng L, Matsui C, Ueda M, Okitsu T, Hatano M, Shimotohno K, Shoji I.
  • Organizer: 2023 International HBV Meeting, 2023
  • Int'l Joint Research
• [Presentation] Identification of DNA repair factors involved in HBV replication using a novel HBV reporter system. (2023)
  • Author(s): Abe T, Nishitsuji H, Ito M, Aly H, Deng L, Matsui C, Shimotohno K, Shoji I.
  • Organizer: 2023 International HBV Meeting
  • Int'l Joint Research
• [Presentation] HCV promotes the selective lysosomal degradation pathways, Chaperone-mediated autophagy and endosomal microautophagy, for viral proliferation (2023)
  • Author(s): Matsui C, Septianastiti MA, Xu Z, Deng L, Abe T, Shoji I
  • Organizer: The 29th International Symposium on Hepatitis C Virus, Flaviviruses, and Related Viruses
  • Int'l Joint Research
• [Presentation] Oxidative stress sensor Keap1 recognizes HBx protein to activate Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication (2023)
  • Author(s): Lin Deng, Adi Ariffianto, Takayuki Abe, Chieko Matsui, Masahiko Ito, Akihide Ryo, Hussein Hassan Aly, Koichi Watashi, Tetsuro Suzuki, Masashi Mizogami, Yoshiharu Matsuura and Ikuo Shoji
  • Organizer: 第70回日本ウイルス学会学術集会
• [Presentation] A novel bile acid derivative inhibits hepatitis B virus infection by disrupting internalization of NTCP and PreS1 complexes at the entry step (2023)
  • Author(s): GN Rsi Suwardana, Takayuki Abe, Daisuke Kuroki, Lin Deng, Chieko Matsui, Masafumi Ueda, Takashi Okitsu, Manabu Hatano, Kunitada Shimotohno, Ikuo Shoji
  • Organizer: 第70回日本ウイルス学会学術集会
• [Presentation] Oxidative Stress Sensor Keap1 Recognizes HBx protein to Activate Nrf2/ARE Signaling Pathway, thereby Inhibiting Hepatitis B Virus Replication (2022)
  • Author(s): Lin Deng, Adi Ariffianto, Chieko Matsui, Takayuki Abe, Masahiko Ito, Tetsuro Suzuki, Yoshiharu Matsuura, and Ikuo Shoji
  • Organizer: 2022 APASL Single Topic Conference on Hepatocellular Carcinoma (2022 APASL STC on HCC)
  • Int'l Joint Research
• [Presentation] Oxidative stress sensor Keap1 recognizes HBx protein to activate Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication (2022)
  • Author(s): Lin Deng, Adi Ariffianto, Chieko Matsui, Takayuki Abe, Masahiko Ito, Tetsuro Suzuki, Yoshiharu Matsuura, and Ikuo Shoji
  • Organizer: 2022 International HBV Meeting
  • Int'l Joint Research
• [Presentation] Oxidative stress sensor Keap1 recognizes HBx protein to activate Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication (2022)
  • Author(s): Adi Ariffianto, Lin Deng, Chieko Matsui, Takayuki Abe, Masahiko Ito, Tetsuro Suzuki, Yoshiharu Matsuura, and Ikuo Shoji
  • Organizer: 第69回日本ウイルス学会学術集会
• [Presentation] A novel bile acid derivative inhibits HBV infection via sodium taurocholate cotransporting polypeptide (2022)
  • Author(s): GN Rsi Suwardana, Takayuki Abe, Kuroki Daisuke, Lin Deng, Chieko Matsui, Masafumi Ueda, Takahashi Okitsu, Manabu Hatano, Kunitada Shimotohno, Ikuo Shoji
  • Organizer: 第69回日本ウイルス学会学術集会
• [Presentation] Hepatitis B virus X protein activates Nrf2/ARE signaling pathway to suppress viral replication. (2021)
  • Author(s): Deng L, Ariffianto A, Liang Y, Matsui C, Abe T, Matsuura Y, Shoji I
  • Organizer: 17th ISVHLD GHS (Global Hepatitis Summit)
  • Int'l Joint Research
• [Presentation] HCV NS3/4A protease cleaves SPG20 for formation of large lipid droplets. (2021)
  • Author(s): Matsui C, Yuliandari P, Deng L, Abe T, Shoji I
  • Organizer: 27th International Symposium on Hepatitis C Virus and Related Viruses
  • Int'l Joint Research
• [Presentation] HCV-induced ROS/JNK signaling pathway activates the E3 ubiquitin ligase Itch to promote the release of HCV particles via polyubiquitylation of VPS4A. (2021)
  • Author(s): Deng L, Liang Y, Ariffianto A, Matsui C, Abe T, Muramatsu M, Wakita T, Shibata H, Maki M, Shoji I.
  • Organizer: 27th International Symposium on Hepatitis C Virus and Related Viruses
  • Int'l Joint Research
• [Presentation] Annexin 5 is involved in the formation of tight junction integrity and negatively regulate HCV propagation. (2021)
  • Author(s): Abe T, Matsui C, Deng L, Matsuura Y, Shoji I
  • Organizer: 27th International Symposium on Hepatitis C Virus and Related Viruses
  • Int'l Joint Research
• [Presentation] Hepatitis C Virus Infection Promotes the Lysosomal Degradation of Diacylglycerol O-acyltransferase 1 (DGAT1). (2021)
  • Author(s): Yuliandari P, Matsui C, Deng L, Abe T, Shoji I
  • Organizer: 27th International Symposium on Hepatitis C Virus and Related Viruses
  • Int'l Joint Research
• [Presentation] Activation of Nrf2/ARE signaling pathway upon hepatitis B virus infection exerts an inhibitory effect on viral replication (2021)
  • Author(s): Ariffianto A, Deng L, Liang Y, Matsui C, Abe T, Matsuura Y, and Shoji I.
  • Organizer: 2021 International HBV Meeting
  • Int'l Joint Research
• [Presentation] Screening for anti-hepatitis B virus activities using heterocyclic compounds and HBV-NanoLuc reporter gene. (2021)
  • Author(s): Abe T, Kuroki D, Matsui C, Deng L, Takeda N, Yasui M, Ueda M, Okitsu T, Yamano Y, Hatano M, Shimotohno K, Shoji I.
  • Organizer: 2021 International HBV Meeting
  • Int'l Joint Research
• [Presentation] Screening for anti-hepatitis B virus activities using heterocyclic compounds and HBV-NanoLuc reporter gene. (2021)
  • Author(s): Abe T, Kuroki D, Matsui C, Deng L, Takeda N, Yasui M, Ueda M, Okitsu T, Yamano Y, Hatano M, Shimotohno K, Shoji I.
  • Organizer: 17th ISVHLD GHS (Global Hepatitis Summit)
  • Int'l Joint Research
• [Presentation] 1.HCV-induced ROS/JNK signaling pathway activates the E3 ubiquitin ligase Itch to promote the release of HCV particles via polyubiquitylation of VPS4A. (2021)
  • Author(s): Deng L, Liang Y, Ariffianto A, Matsui C, Abe T, Muramatsu M, Wakita T, Maki M, Shibata H, and Shoji I.
  • Organizer: 第68回日本ウイルス学会学術集会
• [Presentation] Activation of Nrf2/ARE signaling pathway upon hepatitis B virus infection inhibits viral replication. (2021)
  • Author(s): Ariffianto A, Deng L, Liang Y, Matsui C, Abe T, Matsuura Y, and Shoji I.
  • Organizer: 第68回日本ウイルス学会学術集会
• [Presentation] Annexin 5 is involved in the formation of tight junction integrity and negatively regulate HCV propagation. (2021)
  • Author(s): Abe T, Matsui C, Deng L, Matsuura Y, Shoji I.
  • Organizer: 第68回日本ウイルス学会学術集会
• [Presentation] Hepatitis C Virus Infection Promotes the Lysosomal Degradation of Diacylglycerol O-acyltransferase 1 (DGAT1). (2021)
  • Author(s): Yuliandari P, Matsui C, Deng L, Abe T, Shoji I
  • Organizer: 第68回日本ウイルス学会学術集会
• [Presentation] HCV NS3/4A protease cleaves SPG20 for formation of large lipid droplets. (2021)
  • Author(s): Matsui C, Yuliandari P, Deng L, Abe T, Shoji I.
  • Organizer: 第68回日本ウイルス学会学術集会
• [Remarks] 鄧助教のC型肝炎ウイルスの放出機構に関する総説がVirusesに掲載されました
  • URL: https://www.med.kobe-u.ac.jp/infcon/posts/news72.html
• [Remarks] 鄧助教のHCV粒子放出に関する論文がJournal of Virologyにacceptされました。
  • URL: https://www.med.kobe-u.ac.jp/infcon/posts/news58.html
• [Remarks] 鄧助教の論文がJournal of VirologyのSpotlightに選ばれました。
  • URL: https://www.med.kobe-u.ac.jp/infcon/posts/news59.html
• [Remarks] 鄧助教の論文がJournal of Virologyにacceptされました。
  • URL: https://www.med.kobe-u.ac.jp/infcon/posts/news58.html