Viral regulation of host RNA degradation and its implication on hepatocarcinogenesis.

2021 Fiscal Year Annual Research Report

• Project/Area Number: 19K07586
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: アリ フセインハッサン 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
• Keywords: SKIV2L / HBx / HBV / Viral Life Cycle / RNA Exosome / RNA degradation

Outline of Annual Research Achievements

We found that Hepatitis B x protein significantly induced the expression of the RNA exosome co-factor (SKIV2L) suggesting that HBx expression can possibly regulate the stability of other host /viral mRNA. We analyzed the transcriptome regulated by SKIV2L expression and found that silencing of SKIV2L significantly enhanced the expression of many host interferon stimulated genes (ISGs) and of some cancer regulating genes. Hepatitis Delta Virus (HDV) is a satellite virus which depends on HBV to form its viral particle and spread in nature. Co-infection of HBV and HDV is reported to have more complications and higher levels of cancer development. We found that SKIV2L significantly enhanced HDV replication. By analyzing the ISGs that we found to be regulated by SKIV2L, we found that the ISG OAS2 play important role in this regulation. Since we showed that SKIV2L expression is regulated by HBx, we hypothesized that HBx may play an important role in increased cellular permissiveness to HDV infection by increasing SKIV2L levels and in turn suppressing OAS2 expression. In overexpression experiment, we did not find any significant effect of HBx expression on OAS2 levels. We observed similar results by transfecting HepG2 cells with WT or a mutant form of HBV lacking the expression of HBx. From the previous results we concluded that we could not detect any 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.

Research Products

• [Journal Article] The kinesin KIF4 mediates HBV/HDV entry through the regulation of surface NTCP localization and can be targeted by RXR agonists in vitro (2022)
  • 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 Pages: 「－」
  • DOI: 10.1371/journal.ppat.1009983
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interferon-gamma induced APOBEC3B contributes to Merkel cell polyomavirus genome mutagenesis in Merkel cell carcinoma. (2021)
  • Author(s): Que Lusheng、Li Yingfang、Dainichi Teruki、Kukimoto Iwao、Nishiyama Tomoaki、Nakano Yuri、Shima Kaori、Suzuki Tadaki、Sato Yuko、Horike Shinichi、Aizaki Hideki、Watashi Koichi、Kato Takanobu、Aly Hussein H.、Watanabe Noriyuki、Kabashima Kenji、Wakae Kousho、Muramatsu Masamichi
  • Journal Title: Journal of Investigative Dermatology Volume: 「－」 Pages: 「－」
  • DOI: 10.1016/j.jid.2021.12.019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Current situation of viral hepatitis in Egypt (2021)
  • Author(s): Elbahrawy Ashraf、Ibrahim Marwa K.、Eliwa Ahmed、Alboraie Mohamed、Madian Ali、Aly Hussein Hassan
  • Journal Title: Microbiology and Immunology Volume: 65 Pages: 352～372
  • DOI: 10.1111/1348-0421.12916
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of natural compounds extracted from crude drugs as novel inhibitors of hepatitis C virus (2021)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] MafF Is an Antiviral Host Factor That Suppresses Transcription from Hepatitis B Virus Core Promoter (2021)
  • 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: 95 Pages: 「－」
  • DOI: 10.1128/JVI.00767-21
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Kinesin KIF4 is a key regulator for surface localization of NTCP, and HBV/HDV infection (2021)
  • 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
  • Int'l Joint Research
• [Presentation] Kinesin KIF4 is a possible therapeutic host target and key regulator for surface localization of NTCP, and HBV/HDV infection (2021)
  • 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
• [Presentation] KIF4a, a new host factor required for surface localization of NTCP, and HBV/HDV infection (2021)
  • Author(s): Sameh Ali Gad, Takanobu Kato, Masamichi Muramatsu, Kazuaki Chayama, Takaji Wakita, Hussein H Aly.
  • Organizer: 17th Hiroshima Liver project research center symposium
  • Invited