Correction: IL6 Inhibits HBV Transcription by Targeting the Epigenetic Control of the Nuclear cccDNA Minichromosome

Palumbo, G.A.; Scisciani, C.; Pediconi, Natalia; Lupacchini, Leonardo; Alfaiate, Dulce; Guerrieri, F.; Calvo, Ludovica; Salerno, Debora; Cocco, Silvia Di; Levrero, Massimo; Belloni, Laura

doi:10.1371/journal.pone.0145555

Cited by 4 publications

(5 citation statements)

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“…Generally, the modification of histones plays critical roles in epigenetic regulation and chromatin remodeling, widely affecting gene expression [ 30 – 34 ]. Multiple studies have demonstrated that epigenetic modifications of HBV cccDNA, such as histone modifications and DNA methylation, participate in the regulation of the transcriptional activity of HBV cccDNA [ 35 ]. However, whether the succinylation of histone H3K79 is involved in the transcription of HBV DNA remains unknown.…”

Section: Resultsmentioning

confidence: 99%

IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA

Yuan

Yang

et al. 2020

Clin Epigenet

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Background Hepatitis B virus covalently closed circular DNA (HBV cccDNA) is assembled by histones and non-histones into a chromatin-like cccDNA minichromosome in the nucleus. The cellular histone acetyltransferase GCN5, displaying succinyltransferase activity, is recruited onto cccDNA to modulate HBV transcription in cells. Clinically, IFN-α is able to repress cccDNA. However, the underlying mechanism of IFN-α in the depression of cccDNA mediated by GCN5 is poorly understood. Here, we explored the effect of IFN-α on GCN5-mediated succinylation in the epigenetic regulation of HBV cccDNA minichromosome. Results Succinylation modification of the cccDNA minichromosome has been observed in HBV-infected human liver-chimeric mice and HBV-expressing cell lines. Moreover, histone H3K79 succinylation by GCN5 was identified in the system. Interestingly, the mutant of histone H3K79 efficiently blocked the replication of HBV, and interference with GCN5 resulted in decreased levels of HBV DNA, HBsAg, and HBeAg in the supernatant from de novo HBV-infected HepaRG cells. Consistently, the levels of histone H3K79 succinylation were significantly elevated in the livers of HBV-infected human liver-chimeric mice. The knockdown or overexpression of GCN5 or the mutant of GCN5 could affect the binding of GCN5 to cccDNA or H3K79 succinylation, leading to a change in cccDNA transcription activity. In addition, Southern blot analysis validated that siGCN5 decreased the levels of cccDNA in the cells, suggesting that GCN5-mediated succinylation of histone H3K79 contributes to the epigenetic regulation of cccDNA minichromosome. Strikingly, IFN-α effectively depressed histone H3K79 succinylation in HBV cccDNA minichromosome in de novo HepG2-NTCP and HBV-infected HepaRG cells. Conclusions IFN-α epigenetically regulates the HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA. Our findings provide new insights into the mechanism by which IFN-α modulate the epigenetic regulation of HBV cccDNA minichromosome.

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Section: Resultsmentioning

confidence: 99%

IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA

Yuan

Yang

et al. 2020

Clin Epigenet

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“…TLRs activate intracellular antiviral mechanisms and the production of antiviral effectors, such as IFNs and proinflammatory cytokines. Cytokines, such as interleukin-6 (IL-6) and IL-1β, have been reported to inhibit HBV replication and transcription ( 19 , 20 ). IFNα and IFNβ suppress HBV infection in vitro and in vivo ; thus, these interferons have been used to treat HBV ( 21 , 22 ).…”

Section: Resultsmentioning

confidence: 99%

Hepatitis B virus evades the immune system by suppressing the NF-κB signaling pathway with DENND2A

Ide,

Tabata,

Yonemura

et al. 2024

Microbiol Spectr

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Overcoming hepatitis B virus (HBV) is a challenging problem because HBV deceives the host immune system. We have found that DENN domain-containing 2A (DENND2A) was essential for HBV maintenance, although its role remains unclear. In this study, we elucidate its function by screening a novel DENND2A-binding peptide, DENP4-3S. DENP4-3S exhibits homology to SAM and SH3 domain-containing protein 1 (SASH1), a scaffold protein involved in Toll-like receptor signaling that promotes proinflammatory cytokine production. We confirmed that DENND2A interacts with SASH1 specifically. Overexpression and knockdown experiments showed that overexpression of DENND2A suppressed the transcriptional activity of NF-κB, and the knockdown of DENND2A promoted it and the production of cytokines and interferons. Here, we constructed a fusion protein (10M-DEN3SN) consisting of an anti-asialoglycoprotein receptor antibody and DENP4-3S to deliver the peptide to hepatocytes specifically. 10M-DEN3SN inhibited the interaction between DENND2A and SASH1, and rescued SASH1 trapped by DENND2A, leading to the upregulation of NF-κB and its downstream signaling. In addition, 10M-DEN3SN suppressed HBV proliferation in PXB chimeric mice. These results with the DENND2A-binding peptide delivered into hepatocytes suggested the involvement of DENND2A, SASH, and NF-κB signaling pathway in the HBV infection and onset of hepatitis. In conclusion, this study indicates that HBV utilizes DENND2A and SASH1 to evade the immune system. IMPORTANCE Hepatitis B virus (HBV) is a serious liver infection with no established cure, causing an abnormal host immune response. Here, we identified a novel peptide that interacts with DENN domain-containing 2A (DENND2A), a host factor essential for HBV maintenance. The resulting peptide showed sequence homology, revealing an interaction between DENND2A and the immune system regulator SASH1. This study suggests that DENND2A contributes to HBV infection by suppressing the cellular immune system by inhibiting SASH1. The DENND2A-binding peptide, incorporated into our hepatocyte-specific peptide delivery system, inhibited the DENND2A-SASH1 interaction and promoted the production of cytokines and interferons in cultured hepatocytes. As a consequence, the peptide suppressed HBV proliferation in humanized mice. We report new insights into the role of DENND2A and SASH1 in HBV maintenance and highlight the importance of the immune system.

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“… 37 IL-37 can downregulate proinflammatory factors in liver injury, such as TNF-α, IL-12, IL-6, and IL-17, and upregulate anti-inflammatory factors, such as IL-4 and IL-10. 38 39 IL-4, 40 41 IL-6, 42 43 44 and IL-17 45 inhibit HBV replication and transcription. IL-12 not only promotes cellular immunity, but its combination with other therapies is also beneficial for HBV clearance.…”

Section: Liver Protection By Il-37 In Different Liver Diseasesmentioning

confidence: 99%

Research Progress on the Role and Mechanism of IL-37 in Liver Diseases

Jiang,

Zhou,

Liu

et al. 2023

Semin Liver Dis

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Cytokines are important components of the immune system that can predict or influence the development of liver diseases. IL-37, a new member of the IL-1 cytokine family, exerts potent anti-inflammatory and immunosuppressive effects inside and outside cells. IL-37 expression differs before and after liver lesions, suggesting that it is associated with liver disease; however, its mechanism of action remains unclear. This article mainly reviews the biological characteristics of IL-37, which inhibits hepatitis, liver injury and liver fibrosis by inhibiting inflammation, and inhibits the development of hepatocellular carcinoma (HCC) by regulating the immune microenvironment. Based on additional evidence, combining IL-37 with liver disease markers for diagnosis and treatment can achieve more significant effects, suggesting that IL-37 can be developed into a powerful tool for the clinical adjuvant treatment of liver diseases, especially HCC.

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Correction: IL6 Inhibits HBV Transcription by Targeting the Epigenetic Control of the Nuclear cccDNA Minichromosome

Cited by 4 publications

References 1 publication

IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA

IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA

Hepatitis B virus evades the immune system by suppressing the NF-κB signaling pathway with DENND2A

Research Progress on the Role and Mechanism of IL-37 in Liver Diseases

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