mTOR Signaling: The Interface Linking Cellular Metabolism and Hepatitis B Virus Replication

Wang, Xueyu; Wei, Zhiqiang; Jiang, Yongfang; Zhao, Meng; Lu, Mengji

doi:10.1007/s12250-021-00450-3

Cited by 11 publications

(9 citation statements)

References 130 publications

(175 reference statements)

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“…This finding suggests a significant role of HBV Pol with rt269L in HBx protein stability, irrespective of genotype. The HBx protein has multifaceted roles in HBV-related pathogenesis, including HCC or LC progression, as well as viral replication [33,41,42]. Of note, it has also been reported to play a very pivotal role in mitochondrial quality control via induction of autophagy/mitophagy [31,43] Therefore, the enhanced autophagy/mitophagy induction-mediated improved mitochondrial dynamics and bioenergetics [44] found in rt269L infections in this study (Figs.…”

Section: Discussionmentioning

confidence: 50%

rt269L-Type hepatitis B virus (HBV) in genotype C infection leads to improved mitochondrial dynamics via the PERK–eIF2α–ATF4 axis in an HBx protein-dependent manner

et al. 2023

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Background In our previous report, the rt269I type versus the rt269L type in genotype C2 infection led to poor clinical outcomes and enhanced mitochondrial stress in infected hepatocytes. Here, we sought to investigate differences between the rt269L and rt269I types in mitochondrial functionality in hepatitis B virus (HBV) genotype C2 infection, mainly focusing on endoplasmic reticulum (ER) stress-mediated autophagy induction as an upstream signal. Methods Mitochondrial functionality, ER stress signaling, autophagy induction, and apoptotic cell death between rt269L-type and rt269I-type groups were investigated via in vitro and in vivo experiments. Serum samples were collected from 187 chronic hepatitis patients who visited Konkuk or Seoul National University Hospital. Results Our data revealed that genotype C rt269L versus rt269I infection led to improved mitochondrial dynamics and enhanced autophagic flux, mainly due to the activation of the PERK–eIF2α–ATF4 axis. Furthermore, we demonstrated that the traits found in genotype C rt269L infection were mainly due to increased stability of the HBx protein after deubiquitination. In addition, clinical data using patient sera from two independent Korean cohorts showed that, compared with rt269I, rt269L in infection led to lower 8-OHdG levels, further supporting its improved mitochondrial quality control. Conclusion Our data showed that, compared with the rt269I type, the rt269L type, which presented exclusively in HBV genotype C infection, leads to improved mitochondrial dynamics or bioenergetics, mainly due to autophagy induction via activation of the PERK–eIF2α–ATF4 axis in an HBx protein-dependent manner. This suggests that HBx stability and cellular quality control in the rt269L type predominating in genotype C endemic areas could at least partly contribute to some distinctive traits of genotype C infection, such as higher infectivity or longer duration of the hepatitis B e antigen (HBeAg) positive stage. Graphical Abstract

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Section: Discussionmentioning

confidence: 50%

rt269L-Type hepatitis B virus (HBV) in genotype C infection leads to improved mitochondrial dynamics via the PERK–eIF2α–ATF4 axis in an HBx protein-dependent manner

et al. 2023

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“…Several studies indicated that HBV infection leads to the accumulation of HBsAg in the endoplasmic reticulum and thereby activates the PI3K/Akt/mTOR pathway (Yang et al, 2009). We previously reviewed that mTOR pathway is a central regulator of cell growth, metabolism, proliferation, survival and autophagy and how this pathway is regulated in HBV infection (Wang et al, 2021). AMPK is a sensitive indicator of the cytosolic AMP/ATP ratio (Towler and Hardie, 2007).…”

Section: Discussionmentioning

confidence: 99%

Interferon Alpha Induces Cellular Autophagy and Modulates Hepatitis B Virus Replication

Kemper

Broering

et al. 2022

Front. Cell. Infect. Microbiol.

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Hepatitis B virus (HBV) infection causes acute and chronic liver diseases, including severe hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Interferon alpha 2a (IFNα-2a) is commonly used for treating chronic HBV infection. However, its efficacy remains relatively low. Yet, the immunological and molecular mechanisms for successful IFNα-2a treatment remain elusive. One issue is whether the application of increasing IFNα doses may modulate cellular processes and HBV replication in hepatic cells. In the present study, we focused on the interaction of IFNα signaling with other cellular signaling pathways and the consequence for HBV replication. The results showed that with the concentration of 6000 U/ml IFNα-2a treatment downregulated the activity of not only the Akt/mTOR signaling but also the AMPK signaling. Additionally, IFNα-2a treatment increased the formation of the autophagosomes by blocking autophagic degradation. Furthermore, IFNα-2a treatment inhibited the Akt/mTOR signaling and initiated autophagy under low and high glucose concentrations. In reverse, inhibition of autophagy using 3-methyladenine (3-MA) and glucose concentrations influenced the expression of IFNα-2a-induced ISG15 and IFITM1. Despite of ISGs induction, HBV replication and gene expression in HepG2.2.15 cells, a cell model with continuous HBV replication, were slightly increased at high doses of IFNα-2a. In conclusion, our study indicates that IFNα-2a treatment may interfere with multiple intracellular signaling pathways, facilitate autophagy initiation, and block autophagic degradation, thereby resulting in slightly enhanced HBV replication.

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“…In the current study, the interaction networks of 8 upregulated and 7 downregulated miRNAs with their mRNA targets revealed similar patterns. The KEGG pathway enrichment analysis revealed that the predicted targets of DEmiRNAs were mainly enriched in the following signaling pathways: Wnt signaling pathway [ 29 ], mTOR signaling pathway [ 30 ], phagosome [ 31 ], and cysteine and methionine metabolism [ 32 ], which are related to virus infection.…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of MicroRNA and mRNA Expression Profiles in the Fat Bodies of MbMNPV-Infected Helicoverpa armigera

Liang

Yang

Sun

et al. 2022

Viruses

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MicroRNAs (miRNAs), are a novel class of gene expression regulators, that have been found to participate in regulating host–virus interactions. However, the function of insect-derived miRNAs in response to virus infection is poorly understood. We analyzed miRNA expression profiles in the fat bodies of Helicoverpa armigera (H.armigera) infected with Mamestra brassicae multiple nucleopolyhedroviruses (MbMNPV). A total of 52 differentially expressed miRNAs (DEmiRNAs) were filtered out through RNA-seq analysis. The targets of 52 DEmiRNAs were predicted and 100 miRNA–mRNA interaction pairs were obtained. The predicted targets of DEmiRNAs were mainly enriched in the Wnt signaling pathway, phagosome, and mTOR signaling pathway, which are related to the virus infection. Real-time PCR was used to verify the RNA sequencing results. ame-miR-317-3p, mse-miR-34, novel1-star, and sfr-miR-6094-5p were shown to be involved in the host response to MbMNPV infection. Results suggest that sfr-miR-6094-5p can negatively regulate the expression of four host genes eIF3-S7, CG7583, CG16901, and btf314, and inhibited MbMNPV infection significantly. Further studies showed that RNAi-mediated knockdown of eIF3-S7 inhibited the MbMNPV infection. These findings suggest that sfr-miR-6094-5p inhibits MbMNPV infection by negatively regulating the expression of eIF3-S7. This study provides new insights into MbMNPV and H. armigera interaction mechanisms.

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mTOR Signaling: The Interface Linking Cellular Metabolism and Hepatitis B Virus Replication

Cited by 11 publications

References 130 publications

rt269L-Type hepatitis B virus (HBV) in genotype C infection leads to improved mitochondrial dynamics via the PERK–eIF2α–ATF4 axis in an HBx protein-dependent manner

rt269L-Type hepatitis B virus (HBV) in genotype C infection leads to improved mitochondrial dynamics via the PERK–eIF2α–ATF4 axis in an HBx protein-dependent manner

Interferon Alpha Induces Cellular Autophagy and Modulates Hepatitis B Virus Replication

Integrated Analysis of MicroRNA and mRNA Expression Profiles in the Fat Bodies of MbMNPV-Infected Helicoverpa armigera

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