Cleaved c-FLIP mediates the antiviral effect of TNF-α against hepatitis B virus by dysregulating hepatocyte nuclear factors

Park, Yong Kwang; Park, Eun-Sook; Kim, Doo Hyun; Ahn, Seung Ho; Park, Seung Hwa; Lee, Ah Ram; Park, Soree; Kang, Hong Seok; Lee, Ji‐Hyun; Kim, Jong Man; Lee, Suk-Koo; Lim, Keo-Heun; Isorce, Nathalie; Tong, Shuping; Zoulim, Fabien; Kim, Kyun-Hwan

doi:10.1016/j.jhep.2015.09.012

Cited by 31 publications

(51 citation statements)

References 53 publications

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“…To determine the infection efficiency in PHHs, the cells were infected with various amounts of HBV (100–2000 viral genome equivalents per cell) and were analysed 7 days after infection by measuring the levels of secreted HBeAg and HBsAg 35. The percentage of HBV infection was approximately 90% (figure 7A).…”

Section: Resultsmentioning

confidence: 99%

Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22

Lim

Park

Kim

et al. 2017

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Section: Resultsmentioning

confidence: 99%

Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22

Lim

Park

Kim

et al. 2017

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“…These factors are crucial for HBV clearance, especially at the early phase of HBV infection. TNF-␣ was shown to induce the expression of c-FLIP through the NF-B signaling pathway (46,47), and we also showed that TNF-␣ enhances the generation of p22-FLIP, an N-terminal cleavage product of c-FLIP, which strongly suppresses HBV (18). Because c-FLIP binds to HBx and increases its stability, HBV may have evolved to escape the TNF-␣-induced anti-HBV pressure by hijacking c-FLIP.…”

Section: Discussionmentioning

confidence: 66%

“…HNF1␣ and HNF4␣ are master regulators of hepatocyte differentiation and maintenance (15) and essential for cccDNA transcription (14,16), whereas HNF3␤ is generally known to inhibit HBV transcription (14,17). The expression of these HNFs is regulated by the mitogen-activated protein kinase signaling pathway (18,19). The host proteins which enhance the expression or stability of HNFs are also largely unidentified.…”

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confidence: 99%

“…We previously showed that HBx interacts with c-FLIP and alters the susceptibility to death-inducing signals (25). In addition, we recently found that p22-FLIP, a cleavage product of c-FLIP, forms a ternary complex with HBx and NEMO, which activates NF-B signaling (26) and mediates the TNF-␣-induced suppression of HBV (18). These findings prompted us to investigate the role of c-FLIP in HBV replication and its underlying mechanisms.…”

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

Lee

Lim

Park

et al. 2018

J Virol

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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. 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.

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“…Accumulation of the latter protein is thought to inhibit HBV transcription and replication. 67 Further insights have been provided from animal studies. As previously mentioned, viral clearance, in the chimpanzee model was immediately preceded by a rise in TNF and IFN-γ.…”

Section: The Role Of Tnf In Hbvmentioning

confidence: 99%

The role of tumour necrosis factor in hepatitis B infection: Jekyll and Hyde

et al. 2016

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Chronic hepatitis B (CHB) is a major health problem worldwide and is associated with significant long-term morbidity and mortality. The hepatitis B virus (HBV) is a hepatotropic virus that is capable of integrating in the host nucleus permanently resulting in lifelong infection. To date, there is no definitive cure for HBV, as our current treatments cannot eradicate the viral reservoir that has integrated in the liver. Elucidating the immunopathogenesis is key to finding a therapeutic target for HBV as the virus is not in itself cytopathic but the immune response to the virus causes the majority of the cellular injury. In most cases, the virus reaches a state of equilibrium with low viral replication constrained by host immunity. Multiple cytokines have been implicated in the pathogenesis of CHB. Tumor necrosis factor (TNF) has emerged as a key player; on one hand it can facilitate immune-mediated virological control but on the other hand it can cause collateral hepatocyte damage, cirrhosis and possibly promote hepatocellular carcinoma. In this review, we discuss the current understanding of the immunopathogenesis of HBV, focusing on TNF and whether it can be harnessed in therapeutic strategies to cure HBV infection.

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Cleaved c-FLIP mediates the antiviral effect of TNF-α against hepatitis B virus by dysregulating hepatocyte nuclear factors

Cited by 31 publications

References 53 publications

Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22

Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22

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

The role of tumour necrosis factor in hepatitis B infection: Jekyll and Hyde

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