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 journalArticlepeer-review

    7 Citations (Scopus)


    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
    Issue number16
    Publication statusPublished - 2018 Aug 1


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

    ASJC Scopus subject areas

    • Microbiology
    • Immunology
    • Insect Science
    • Virology


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