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Multiple Functions of Cellular FLIP Are Essential for Replication of Hepatitis B Virus.

Published on Jun 6, 2018in Journal of Virology4.324
· DOI :10.1128/JVI.00339-18
Ah Ram Lee7
Estimated H-index: 7
(Konkuk University),
Keo Heun Lim1
Estimated H-index: 1
(Konkuk University)
+ 12 AuthorsKyun-Hwan Kim22
Estimated H-index: 22
(Konkuk University)
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. 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.
  • References (71)
  • Citations (1)
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References71
Newest
#1Keo Heun Lim (Konkuk University)H-Index: 1
#2Eun-Sook Park (Konkuk University)H-Index: 11
Last. Kyun-Hwan Kim (Konkuk University)H-Index: 22
view all 23 authors...
Objective Interferons (IFNs) mediate direct antiviral activity. They play a crucial role in the early host immune response against viral infections. However, IFN therapy for HBV infection is less effective than for other viral infections. Design We explored the cellular targets of HBV in response to IFNs using proteome-wide screening. Results Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells. We found several IFN...
18 CitationsSource
#1Shixiong Lei (Fourth Military Medical University)H-Index: 3
#2Jiandong YangH-Index: 9
Last. Xilin Du (Fourth Military Medical University)H-Index: 11
view all 11 authors...
Background Tumor cells use aerobic glycolysis to rapidly generate ATP and growth substrate which expenses a large amount of glucose. However, how tumor cells take in enough glucose from the tumor microenvironment of insufficient blood supply remains poorly understood. The cellular FLICE-like inhibitory protein (FLIP), a cell apoptosis inhibiting molecule, is highly expressed in hepatocellular carcinoma (HCC) and is implicated in HCC development.
3 CitationsSource
#1Gu Choul Shin (Konkuk University)H-Index: 12
#2Hong Seok Kang (Konkuk University)H-Index: 8
Last. Kyun-Hwan Kim (Konkuk University)H-Index: 22
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ABSTRACTDeath receptors of TNFSF10/TRAIL (tumor necrosis factor superfamily member 10) contribute to immune surveillance against virus-infected or transformed cells by promoting apoptosis. Many viruses evade antiviral immunity by modulating TNFSF10 receptor signaling, leading to persistent infection. Here, we report that hepatitis B virus (HBV) X protein (HBx) restricts TNFSF10 receptor signaling via macroautophagy/autophagy-mediated degradation of TNFRSF10B/DR5, a TNFSF10 death receptor, and th...
15 CitationsSource
#1Christopher M. Murphy (UNC: University of North Carolina at Chapel Hill)H-Index: 3
#2Yanping Xu (UNC: University of North Carolina at Chapel Hill)H-Index: 1
Last. Lishan Su (UNC: University of North Carolina at Chapel Hill)H-Index: 38
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Summary The hepatitis B virus (HBV) regulatory protein X (HBx) activates gene expression from the HBV covalently closed circular DNA (cccDNA) genome. Interaction of HBx with the DDB1-CUL4-ROC1 (CRL4) E3 ligase is critical for this function. Using substrate-trapping proteomics, we identified the structural maintenance of chromosomes (SMC) complex proteins SMC5 and SMC6 as CRL4 HBx substrates. HBx expression and HBV infection degraded the SMC5/6 complex in human hepatocytes in vitro and in humaniz...
58 CitationsSource
#1Doo Hyun KimH-Index: 9
#2Hong Seok KangH-Index: 8
Last. Kyun-Hwan KimH-Index: 22
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Approximately 350 million people are estimated to be persistently infected with hepatitis B virus (HBV) worldwide. HBV maintains persistent infection by employing covalently closed circular DNA (cccDNA), a template for all HBV RNAs. Chronic hepatitis B (CHB) patients are currently treated with nucleos(t)ide analogs such as lamivudine, adefovir, entecavir, and tenofovir. However, these treatments rarely cure CHB because they are unable to inhibit cccDNA transcription and inhibit only a late stage...
9 CitationsSource
#1Valentina AlarconH-Index: 1
#2Sergio Hernández (Andrés Bello National University)H-Index: 7
Last. Alejandra LoyolaH-Index: 16
view all 10 authors...
With about 350 million people chronically infected around the world hepatitis B is a major health problem. Template for progeny HBV synthesis is the viral genome, organized as a minichromosome (cccDNA) inside the hepatocyte nucleus. How viral cccDNA gene expression is regulated by its chromatin structure; more importantly, how the modulation of this structure impacts on viral gene expression remains elusive. Here, we found that the enzyme SetDB1 contributes to setting up a repressed cccDNA chrom...
12 CitationsSource
#1Adrien DecorsiereH-Index: 2
#2Henrik MuellerH-Index: 6
Last. Michel StrubinH-Index: 28
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Chronic hepatitis B virus infection is a leading cause of cirrhosis and liver cancer. Hepatitis B virus encodes the regulatory HBx protein whose primary role is to promote transcription of the viral genome, which persists as an extrachromosomal DNA circle in infected cells. HBx accomplishes this task by an unusual mechanism, enhancing transcription only from extrachromosomal DNA templates. Here we show that HBx achieves this by hijacking the cellular DDB1-containing E3 ubiquitin ligase to target...
124 CitationsSource
#1Yong Kwang Park (Konkuk University)H-Index: 11
#2Eun-Sook Park (Konkuk University)H-Index: 11
Last. Kyun-Hwan Kim (Konkuk University)H-Index: 22
view all 16 authors...
Background & Aims Cytokines are key molecules implicated in the defense against virus infection. Tumor necrosis factor-alpha (TNF-α) is well known to block the replication of hepatitis B virus (HBV). However, the molecular mechanism and the downstream effector molecules remain largely unknown. Methods In this study, we investigated the antiviral effect and mechanism of p22-FLIP (FLICE-inhibitory protein) by ectopic expression in vitro and in vivo . In addition, to provide the biological relevanc...
12 CitationsSource
#1Valerio Giacomo Minero (UNITO: University of Turin)H-Index: 13
#2D. De Stefanis (UNITO: University of Turin)H-Index: 2
Last. Gabriella Bonelli (UNITO: University of Turin)H-Index: 24
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High mortality among hepatocellular carcinoma (HCC) patients reflects both late diagnosis and low curability, due to pharmacoresistance. Taxol (TAX) is toxic for many human HCC-derived cell lines, yet its clinical efficacy on HCCs is poor. Combining TAX with other drugs appears a promising possibility to overcome such refractoriness. We analyzed whether combining tumor necrosis factor (TNF) with TAX would improve their toxicity. Human HCC-derived cell lines were treated with TAX or TNF, alone or...
6 CitationsSource
#1Bo Ye (ZJU: Zhejiang University)H-Index: 8
#2Xianbao Liu (ZJU: Zhejiang University)H-Index: 16
Last. Yunbo Chen (ZJU: Zhejiang University)H-Index: 13
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Hepatitis B virus (HBV) infection is the major cause of inflammatory liver disease, of which the clinical recovery and effective anti-viral therapy is associated with the sustained viral control of effector T cells. In humans, chronic HBV infection often shows weak or absent virus-specific T-cell reactivity, which is described as the ‘exhaustion' state characterized by poor effector cytotoxic activity, impaired cytokine production and sustained expression of multiple inhibitory receptors, such a...
98 CitationsSource
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#1Soree Park (Konkuk University)H-Index: 8
#2Yea Na Ha (Konkuk University)H-Index: 3
Last. Jae Jin Shin (Konkuk University)
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Hepatitis B virus (HBV) infection is a major factor in the development of various liver diseases such as hepatocellular carcinoma (HCC). Among HBV encoded proteins, HBV X protein (HBx) is known to play a key role in the development of HCC. Hepatocyte nuclear factor 4α (HNF4α) is a nuclear transcription factor which is critical for hepatocyte differentiation. However, the expression level as well as its regulatory mechanism in HBV infection have yet to be clarified. Here, we observed the suppress...
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#1Fanyun KongH-Index: 5
#2Hongjuan YouH-Index: 5
Last. Renxian TangH-Index: 11
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The ubiquitin proteasome system (UPS) regulates the expression levels of cellular proteins by ubiquitination of protein substrates followed by their degradation via the proteasome. As a highly conserved cellular degradation mechanism, the UPS affects a variety of biological processes and participates in viral propagation. During hepatitis B virus (HBV) infection, the UPS is shown to act as a double-edged sword in viral pathogenesis. On the one hand, the UPS acts as a host defense mechanism to se...
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