Multiple Functions of Cellular FLIP Are Essential for Replication of Hepatitis B Virus
| Autor: | Gu Choul Shin, Doo Hyun Kim, Soree Park, Kyun-Hwan Kim, Ah Ram Lee, Byeongjune Jae, Keo Heun Lim, Heewoo Sim, Yong Kwang Park, Yea Na Ha, Juhee Won, Hong Seok Kang, Seong Il Choi, Eun Sook Park, Dong-Sik Kim |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Hepatitis B virus Immunology CASP8 and FADD-Like Apoptosis Regulating Protein Biology Virus Replication medicine.disease_cause Microbiology Virus 03 medical and health sciences Transcription (biology) Virology Transcriptional regulation medicine Humans Viral Regulatory and Accessory Proteins Gene knockdown virus diseases digestive system diseases Virus-Cell Interactions Cell biology Hepatocyte nuclear factors HBx 030104 developmental biology Viral replication Gene Knockdown Techniques Insect Science Host-Pathogen Interactions Hepatocytes Trans-Activators |
| Zdroj: | Journal of Virology. 92 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.00339-18 |
| Popis: | 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.IMPORTANCE Although the chronic hepatitis B virus (HBV) infection still poses a major health concern, the host factors which are required for the replication of HBV are largely uncharacterized. Our studies identify cellular FLICE inhibitory protein (c-FLIP) as an essential factor in HBV replication. We found the dual roles of c-FLIP in regulation of HBV replication: c-FLIP interacts with HBx and enhances its stability and regulates the expression or stability of hepatocyte nuclear factors which are essential for transcription of HBV genome. Our findings may provide a new target for intervention in persistent HBV infection. |
| Databáze: | OpenAIRE |
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