Forkhead O Transcription Factor 4 Restricts HBV Covalently Closed Circular DNA Transcription and HBV Replication through Genetic Downregulation of Hepatocyte Nuclear Factor 4 Alpha and Epigenetic Suppression of Covalently Closed Circular DNA via Interacting with Promyelocytic Leukemia Protein

Li, Yuqi; He, Minjing; Gong, Ruijie; Wang, Ziteng; Lü, Lin; Peng, Shushi; Duan, Zhiyun; Feng, Ying; Liu, Yi; Gao, Bo

doi:10.1128/jvi.00546-22

Cited by 11 publications

(6 citation statements)

References 55 publications

(100 reference statements)

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“…In our analyses, most of HBV-induced 53BP1 foci colocalized with PML signal. Interestingly, some studies indicated that, in the absence of HBx, PML bodies are important for HBV transcriptional silencing by recruiting inhibitory factors and viral genomes (Niu et al, 2017;Li et al, 2022;Yao et al, 2023a). It would be interesting to perform immune-FISH analyses, able to discriminate between rc and cccDNA, to determine whether PML/53BP1 signals also associate to viral DNA or whether they represent an alternative nuclear anti-viral structure.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the phospho-signature induced by hepatitis B virus in primary human hepatocytes

Pastor,

Charles,

Belmudes

et al. 2024

Preprint

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Phosphorylation is a major post-translation modification (PTM) of proteins, and small molecules, which is finely tuned by the activity of several hundred kinases and phosphatases. It controls most if not all cellular pathways including anti-viral responses. Accordingly, viruses often induce important changes in the phosphorylation of host factors that can either help or counteract viral replication. Among more than 500 kinases constituting the human kinome only few have been described as important for the Hepatitis B virus (HBV) infectious cycle, and most of them intervene during early or late infectious steps by phosphorylating the viral Core protein (HBc) protein. In addition, scarce information is available on the consequences of HBV infection on the activity of cellular kinases. The objective of this study was to investigate the global impact of HBV infection on the cellular phosphorylation landscape at early after infection. For this, primary human hepatocytes (PHH) were challenged or not with HBV, and a mass spectrometry (MS)-based quantitative phosphoproteomic analysis was conducted two- and seven-days post-infection. The results indicated that while, as expected, HBV infection only minimally modified the cell proteome, important changes were observed on the phosphorylation level of several host proteins at both times points. Gene enrichment and ontology analyses of up- and down- phosphorylated proteins revealed common and distinct signatures induced following infection. In particular, HBV infection resulted in up-phosphorylation of proteins involved in DNA damage signaling and repair, RNA metabolism, in particular splicing, and cytoplasmic cell-signaling. Several down-phosphorylated factors, mostly involved in cell signaling and communication, were also detected. Validation studies performed on some selected up-phosphorylated proteins, revealed that HBV infection induced a DNA damage response characterized by the appearance of 53BP1 foci, whose siRNA-mediated knock-down increased cccDNA levels. In addition, among up-phosphorylated RBPs, SRRM2, a major scaffold of nuclear speckles behaved as antiviral factor. In accordance with these findings, kinase prediction analysis indicated that HBV infection upregulates the activity of major kinases involved in DNA repair. These results strongly suggest that HBV infection triggers an intrinsic anti-viral response composed by DNA repair factors and RBPs that contribute to reduce HBV replication in cell culture models.

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Section: Discussionmentioning

confidence: 99%

Deciphering the phospho-signature induced by hepatitis B virus in primary human hepatocytes

Pastor,

Charles,

Belmudes

et al. 2024

Preprint

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“…Also, Sp100A, a PML-NB protein, recruits the heterochromatin protein 1 alpha (HP1α) to condense viral DNA, leading to transcriptional repression of the AdV genome [ 22 ]. FOXO4, a PML-NB-associated transcription factor, was found to promote heterochromatinization and silencing of hepatitis B virus (HBV) DNA [ 40 ]. In addition, the structural maintenance of chromosome 5 and 6 (Smc5/6) proteins, which also localize with PML-NBs in human hepatocytes, has been reported to act as RFs for HBV transcription by altering their chromatin organization [ 34 , 41 , 42 ].…”

Section: Virus Epigenetic Restriction Factors (Erfs)mentioning

confidence: 99%

Epigenetic Restriction Factors (eRFs) in Virus Infection

Roy,

Ghosh

2024

Viruses

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The ongoing arms race between viruses and their hosts is constantly evolving. One of the ways in which cells defend themselves against invading viruses is by using restriction factors (RFs), which are cell-intrinsic antiviral mechanisms that block viral replication and transcription. Recent research has identified a specific group of RFs that belong to the cellular epigenetic machinery and are able to restrict the gene expression of certain viruses. These RFs can be referred to as epigenetic restriction factors or eRFs. In this review, eRFs have been classified into two categories. The first category includes eRFs that target viral chromatin. So far, the identified eRFs in this category include the PML-NBs, the KRAB/KAP1 complex, IFI16, and the HUSH complex. The second category includes eRFs that target viral RNA or, more specifically, the viral epitranscriptome. These epitranscriptomic eRFs have been further classified into two types: those that edit RNA bases—adenosine deaminase acting on RNA (ADAR) and pseudouridine synthases (PUS), and those that covalently modify viral RNA—the N6-methyladenosine (m6A) writers, readers, and erasers. We delve into the molecular machinery of eRFs, their role in limiting various viruses, and the mechanisms by which viruses have evolved to counteract them. We also examine the crosstalk between different eRFs, including the common effectors that connect them. Finally, we explore the potential for new discoveries in the realm of epigenetic networks that restrict viral gene expression, as well as the future research directions in this area.

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“…Triplex sequence proteins (TRIMs) area family of proteins that play an important role in antiviral innate immunity, and members can effectively inhibit HBV. It has been found that TRIM19 [11] and TRIM38 [12] can inhibit HBV and can be induced by IFN-α. In a study followed for 11.5 years [13], higher rates of HBeAg serologic conversion and negative HBsAg conversion were observed in HBeAg-positive hepatitis B patients treated with interferon, while no significant difference in rates of HBsAg loss was observed between patients treated with short-term and long-term therapy.…”

Section: Interferon Monotherapymentioning

confidence: 99%

Research Progress of Interferon in the Treatment of Liver Cancer

Xie,

Xu,

Pan

2024

IJCEMR

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Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor in the world and the fourth leading cause of cancer-related death. It is characterized by high incidence, poor prognosis, and high recurrence rates. Most patients are in an advanced stage when they seek treatment, and the therapeutic effect is not satisfactory. Interferon (IFNs) is a kind of cytokine with anti-virus, inhibition of cell proliferation, and induction of apoptosis, which has the advantages of improving cure rate, safe withdrawal of the drug, achieving sustained nontherapeutic immune response, reducing the incidence of liver cancer and avoiding the occurrence of drug resistance, delaying the progression of disease and improving the quality of life. Recent studies have found that IFNs can prevent the occurrence of viral hepatitis-related liver cancer and the recurrence and metastasis of liver cancer after surgery. Still, at the same time, there are also adverse reactions. This article reviews the mechanism of action, treatment, and adverse reactions of IFNs in liver cancer.

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Forkhead O Transcription Factor 4 Restricts HBV Covalently Closed Circular DNA Transcription and HBV Replication through Genetic Downregulation of Hepatocyte Nuclear Factor 4 Alpha and Epigenetic Suppression of Covalently Closed Circular DNA via Interacting with Promyelocytic Leukemia Protein

Abstract: HBV cccDNA is a determining factor for viral persistence and the main obstacle for a cure of chronic hepatitis B. Strategies that target cccDNA directly are therefore of great importance in controlling persistent HBV infection.

Cited by 11 publications

References 55 publications

Deciphering the phospho-signature induced by hepatitis B virus in primary human hepatocytes

Deciphering the phospho-signature induced by hepatitis B virus in primary human hepatocytes

Epigenetic Restriction Factors (eRFs) in Virus Infection

Research Progress of Interferon in the Treatment of Liver Cancer

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