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Viral regulation of host RNA degradation and its implication on hepatocarcinogenesis

Research Project

Project/Area Number 19K07586
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49060:Virology-related
Research InstitutionNational Institute of Infectious Diseases

Principal Investigator

Aly Hussein H  国立感染症研究所, ウイルス第二部, 主任研究官 (00523515)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
KeywordsSKIV2L / HBV / RNA degradation / HBx / Viral Life Cycle / RNA Exosome / Ski2 / Viral life cycle / Hepatitis B Virus / Virology
Outline of Research at the Start

By controlling mRNA stability, the virus can manipulate several cellular responses, and cellular environment to favor its persistence. This manipulation may lead to continuous alteration of cellular environment and cancer development. We found that hepatitis B virus can control the expression of Ski2 leading to the degradation of HBx mRNA at the Ski2/RNA exosome system. Using in-vitro and in-vivo mouse model systems, we aim to analyze the functional significance of regulating this RNA degradation mechanism on HBV persistence, and its possible contribution to HBV-induced hepatocarcinogenesis.

Outline of Final Research Achievements

We found that HBx protein significantly induced the expression of the RNA exosome co-factor (SKIV2L) suggesting that it may regulate the stability of other host /viral mRNA. Silencing of SKIV2L significantly enhanced the expression of OAS2. Hepatitis Delta Virus (HDV) is a satellite virus that depends on HBV. We found that SKIV2L significantly induced HDV replication. OAS2 played important role in this regulation. We hypothesized that HBx may increase cellular permissiveness to HDV infection by increasing SKIV2L levels and in turn suppressing OAS2 expression. We did not find any significant effect of HBx expression on OAS2 levels. We observed similar results by transfecting WT or a mutant HBV lacking the expression of HBx. From these results we concluded that there are no significant effect of SKIV2L on the HBx-mediated changes in cellular transcriptome. We also found that SKIV2L plays an important role in supporting HDV infection by suppressing host ISGs especially OAS2.

Academic Significance and Societal Importance of the Research Achievements

We found that the RNA exosome co-factor (SKIV2L) regulate Hepatitis Delta Virus (HDV) replication by the suppression of interferon stimulated gene (OAS2) expression.

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (16 results)

All 2022 2021 2020 2019

All Journal Article (9 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 9 results,  Open Access: 5 results) Presentation (7 results) (of which Int'l Joint Research: 4 results,  Invited: 1 results)

  • [Journal Article] The kinesin KIF4 mediates HBV/HDV entry through the regulation of surface NTCP localization and can be targeted by RXR agonists in vitro2022

    • Author(s)
      Gad Sameh A.、Sugiyama Masaya、Tsuge Masataka、Wakae Kosho、Fukano Kento、Oshima Mizuki、Sureau Camille、Watanabe Noriyuki、Kato Takanobu、Murayama Asako、Li Yingfang、Shoji Ikuo、Shimotohno Kunitada、Chayama Kazuaki、Muramatsu Masamichi、Wakita Takaji、Nozaki Tomoyoshi、Aly Hussein H.
    • Journal Title

      PLOS Pathogens

      Volume: 18 Issue: 3 Pages: 1-26

    • DOI

      10.1371/journal.ppat.1009983

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Interferon-gamma induced APOBEC3B contributes to Merkel cell polyomavirus genome mutagenesis in Merkel cell carcinoma2021

    • Author(s)
      Que L, Li Y, Dainichi T, Kukimoto I, Nishiyama T, Nakano Y, Shima K, Suzuki T, Sato Y, Horike S, Aizaki H, Watashi K, Kato T, Aly HH, Watanabe N, Kabashima K, Wakae K, Muramatsu M.
    • Journal Title

      J Invest Dermatol

      Volume: S0022-202X(21) Issue: 7 Pages: 02636-1

    • DOI

      10.1016/j.jid.2021.12.019

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Current situation of viral hepatitis in Egypt2021

    • Author(s)
      Elbahrawy Ashraf、Ibrahim Marwa K.、Eliwa Ahmed、Alboraie Mohamed、Madian Ali、Aly Hussein Hassan
    • Journal Title

      Microbiology and Immunology

      Volume: 「-」 Issue: 9 Pages: 352-372

    • DOI

      10.1111/1348-0421.12916

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Identification of natural compounds extracted from crude drugs as novel inhibitors of hepatitis C virus2021

    • Author(s)
      Zheng Xin、Guo Rui、Liu Qingbo、Wakae Kousho、Watanabe Noriyuki、Fukano Kento、Que Lusheng、Li Yingfang、Aly Hussein H.、Watashi Koichi、Suzuki Ryosuke、Murayama Asako、Kato Takanobu、Aizaki Hideki、Wakita Takaji、Huang Xiaoxiao、Yan Yi、Song Shao-Jiang、Muramatsu Masamichi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 567 Pages: 1-8

    • DOI

      10.1016/j.bbrc.2021.06.022

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] MafF is an antiviral host factor that suppresses transcription from Hepatitis B Virus core promoter2021

    • Author(s)
      Ibrahim Marwa K.、Abdelhafez Tawfeek H.、Takeuchi Junko S.、Wakae Kosho、Sugiyama Masaya、Tsuge Masataka、Ito Masahiko、Watashi Koichi、El Kassas Mohamed、Kato Takanobu、Murayama Asako、Suzuki Tetsuro、Chayama Kazuaki、Shimotohno Kunitada、Muramatsu Masamichi、Aly Hussein H.、Wakita Takaji
    • Journal Title

      Journal of Virology

      Volume: 「-」 Issue: 15

    • DOI

      10.1128/jvi.00767-21

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] N‐terminal PreS1 Sequence Regulates Efficient Infection of Cell Culture‐generated Hepatitis B Virus2020

    • Author(s)
      Murayama A、Yamada N、Osaki 、Shiina 、Aly H H、Iwamoto M、Tsukuda S、Watashi K、Matsuda M、Suzuki R、Tanaka T、Moriishi K、Suzuki T、Nishitsuji H、Sugiyama M、Mizokami M、Shimotohno K、Wakita T、Muramatsu M、Liang T J、Kato T
    • Journal Title

      Hepatology

      Volume: 「-」 Issue: 2 Pages: 520-532

    • DOI

      10.1002/hep.31308

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Anti‐viral effects of interferon‐λ3 on hepatitis B virus infection in cell culture2020

    • Author(s)
      Yamada Norie、Murayama Asako、Shiina Masaaki、Aly Hussein Hassan、Iwamoto Masashi、Tsukuda Senko、Watashi Koichi、Tanaka Tomohisa、Moriishi Kohji、Nishitsuji Hironori、Sugiyama Masaya、Mizokami Masashi、Shimotohno Kunitada、Muramatsu Masamichi、Murata Kazumoto、Kato Takanobu
    • Journal Title

      Hepatology Research

      Volume: 50 Issue: 3 Pages: 283-291

    • DOI

      10.1111/hepr.13449

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] MCPIP1 reduces HBV-RNA by targeting its epsilon structure2020

    • Author(s)
      Li Yingfang、Que Lusheng、Fukano Kento、Koura Miki、Kitamura Kouichi、Zheng Xin、Kato Takanobu、Aly Hussein Hassan、Watashi Koichi、Tsukuda Senko、Aizaki Hideki、Watanabe Noriyuki、Sato Yuko、Suzuki Tadaki、Suzuki Hiroshi I.、Hosomichi Kazuyoshi、Kurachi Makoto、Wakae Kousho、Muramatsu Masamichi
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 20763-20763

    • DOI

      10.1038/s41598-020-77166-z

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hepatitis B Virus Genotype-Dependent Vulnerability of Infected Cells to Immune Reaction in the Early Phase of Infection2019

    • Author(s)
      Shiina Masaaki、Yamada Norie、Sugiyama Ryuichi、Murayama Asako、Aly Hussein Hassan、Muramatsu Masamichi、Wakita Takaji、Imawari Michio、Kato Takanobu
    • Journal Title

      Frontiers in Microbiology

      Volume: 10

    • DOI

      10.3389/fmicb.2019.02427

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Kinesin KIF4 is a key regulator for surface localization of NTCP, and HBV/HDV infection2021

    • Author(s)
      Sameh A. Gad, Masaya Sugiyama, Masataka Tsuge, Kosho Wakae, Kento Fukano, Noriyuki Watanabe, Takanobu Kato, Asako Murayama, Yingfang Li, Ikuo Shoji, Kunitada Shimotohno, Kazuaki Chayama, Masamichi Muramatsu, Takaji Wakita, Tomoyoshi Nozaki, Hussein H. Aly
    • Organizer
      2021 International Meeting, Biology of the Hepatitis B and D Viruses
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Kinesin KIF4 is a possible therapeutic host target and key regulator for surface localization of NTCP, and HBV/HDV infection2021

    • Author(s)
      Sameh A. Gad, Masaya Sugiyama, Masataka Tsuge, Kosho Wakae, Kento Fukano, Noriyuki Watanabe, Takanobu Kato, Asako Murayama, Yingfang Li, Ikuo Shoji, Kunitada Shimotohno, Kazuaki Chayama, Masamichi Muramatsu, Takaji Wakita, Tomoyoshi Nozaki, Hussein H. Aly
    • Organizer
      The 68th Annual Meeting of the Japanese Society for Virology
    • Related Report
      2021 Annual Research Report
  • [Presentation] KIF4a, a new host factor required for surface localization of NTCP, and HBV/HDV infection2021

    • Author(s)
      Sameh Ali Gad, Takanobu Kato, Masamichi Muramatsu, Kazuaki Chayama, Takaji Wakita, Hussein H Aly.
    • Organizer
      17th Hiroshima Liver project research center symposium
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] The IL-1 β induced (MafF) is an important regulator of HBV core promoter activity2020

    • Author(s)
      Marwa K. Ibrahim, Sameh A. Gad, Koichi Watashi, Li Yingfang, Masaya Sugiyama, Masahiko Ito, Asako Murayama, Tetsuro Suzuki, Takanobu Kato, Kunitada Shimotohno, Masamichi Muramatsu, Takaji Wakita, Hussein H. Aly.
    • Organizer
      The 67th Annual Meeting of the Japanese Society for Virology.
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] MafF is a key player of IL-1β-induced suppression of transcription from HBV-core promoter, and the resulting suppression of viral replication2019

    • Author(s)
      2.Marwa K. Ibrahim, Sameh A. Gad, Koichi Watashi, Li Yingfang, Masaya Sugiyama, Masahiko Ito, Asako Murayama, Tetsuro Suzuki, Takanobu Kato, Kunitada Shimotohno, Masamichi Muramatsu, Takaji Wakita, Hussein H. Aly.
    • Organizer
      2019 International Meeting, molecular Biology of Hepatitis B virus
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] The IL-1 β induced (MafF) is an important regulator of HBV core promoter activity.2019

    • Author(s)
      1.Marwa K. Ibrahim, Sameh A. Gad, Koichi Watashi, Li Yingfang, Masaya Sugiyama, Masahiko Ito, Asako Murayama, Tetsuro Suzuki, Takanobu Kato, Kunitada Shimotohno, Masamichi Muramatsu, Takaji Wakita, Hussein H. Aly
    • Organizer
      The 67th Annual Meeting of the Japanese Society for Virology.
    • Related Report
      2019 Research-status Report
  • [Presentation] MAFF IS AN IMPORTANT REGULATOR OF HBV CORE PROMOTER ACTIVITY, AND HBV REPLICATION2019

    • Author(s)
      Marwa K. Ibrahim, Sameh A. Gad, Koichi Watashi, Takanobu Kato, Asako Murayama, Kunitada Shimotohno, Takaji Wakita, Masamichi Muramatsu, Hussein H. Aly
    • Organizer
      The Liver Meeting 2019, The 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2023-01-30  

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