Multiple functions of cellular FLIP are essential for replication of hepatitis B virus

Ah Ram Lee, Keo Heun Lim, Eun Sook Park, Doo Hyun Kim, Yong Kwang Park, Soree Park, Dong-Sik Kim, Gu Choul Shin, Hong Seok Kang, Juhee Won, Heewoo Sim, Yea Na Ha, Byeongjune Jae, Seong Il Choi, Kyun Hwan Kim

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Hepatitis B virus (HBV) infection is a leading cause of liver diseases; however, the host factors which facilitate the replication and persistence of HBV are largely unidentified. Cellular FLICE inhibitory protein (c-FLIP) is a typical antiapoptotic protein. In many cases of liver diseases, the expression level of c-FLIP is altered, which affects the fate of hepatocytes. We previously found that c-FLIP and its cleaved form interact with HBV X protein (HBx), which is essential for HBV replication, and regulate diverse cellular signals. In this study, we investigated the role of endogenous c-FLIP in HBV replication and its underlying mechanisms. The knockdown of endogenous c-FLIP revealed that this protein regulates HBV replication through two different mechanisms. (i) c-FLIP interacts with HBx and protects it from ubiquitin-dependent degradation. The N-terminal DED1 domain of c-FLIP is required for HBx stabilization. (ii) c-FLIP regulates the expression or stability of hepatocyte nuclear factors (HNFs), which have critical roles in HBV transcription and maintenance of hepatocytes. c-FLIP regulates the stability of HNFs through physical interactions. We verified our findings in three HBV infection systems: HepG2-NTCP cells, differentiated HepaRG cells, and primary human hepatocytes. In conclusion, our results identify c-FLIP as an essential factor in HBV replication. c-FLIP regulates viral replication through its multiple effects on viral and host proteins that have critical roles in HBV replication.

Original languageEnglish
Article numbere00339-18
JournalJournal of Virology
Volume92
Issue number16
DOIs
Publication statusPublished - 2018 Aug 1

Keywords

  • C-FLIP
  • HBx
  • Hepatitis B virus
  • Hepatocyte nuclear factor
  • Transcriptional control

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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  • Cite this

    Lee, A. R., Lim, K. H., Park, E. S., Kim, D. H., Park, Y. K., Park, S., Kim, D-S., Shin, G. C., Kang, H. S., Won, J., Sim, H., Ha, Y. N., Jae, B., Choi, S. I., & Kim, K. H. (2018). Multiple functions of cellular FLIP are essential for replication of hepatitis B virus. Journal of Virology, 92(16), [e00339-18]. https://doi.org/10.1128/JVI.00339-18