HCV-induced oxidative stress by inhibition of Nrf2 triggers autophagy and favors release of viral particles

Medvedev, Regina; Ploen, Daniela; Spengler, Catrina; Elgner, Fabian; Ren, Huimei; Bunten, Sarah; Hildt, Eberhard

doi:10.1016/j.freeradbiomed.2017.06.021

Cited by 55 publications

(52 citation statements)

References 67 publications

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“…On the other hand, HCV core impairs the Nrf2/ARE signaling pathway by inducing the translocation of sMaf proteins in the cytoplasm, where they bind to NS3 as part of the replication complex. As a result, Nrf2 is trapped in the cytoplasm and is unable to function as transcription factor [26,30].…”

Section: Introductionmentioning

confidence: 99%

“…It has been recently demonstrated that higher expression of nuclear Nrf2 contributes to persistent HCV infection and that knockdown of Nrf2 suppresses its persistent infection [62]. The authors suggest that the nuclear translocation of p-Nrf2 might play an important role in the expression of the genes which contribute to regulate apoptosis and HCV persistence [25,26,30,62]. Accordingly, we found higher mRNA levels of GCL and GS enzymes during the recovery period; at the same time, Nrf2 protein content was highly expressed during the chronic phase.…”

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confidence: 99%

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Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Anticoli

Amatore

Matarrese

et al. 2019

Oxidative Medicine and Cellular Longevity

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Hepatitis C virus (HCV) is a blood-borne pathogen causing acute and chronic hepatitis. A significant number of people chronically infected with HCV develop cirrhosis and/or liver cancer. The pathophysiologic mechanisms of hepatocyte damage associated with chronic HCV infection are not fully understood yet, mainly due to the lack of an in vitro system able to recapitulate the stages of infection in vivo. Several studies underline that HCV virus replication depends on redox-sensitive cellular pathways; in addition, it is known that virus itself induces alterations of the cellular redox state. However, the exact interplay between HCV replication and oxidative stress has not been elucidated. In particular, the role of reduced glutathione (GSH) in HCV replication and infection is still not clear. We set up an in vitro system, based on low m.o.i. of Huh7.5 cell line with a HCV infectious clone (J6/JFH1), that reproduced the acute and persistent phases of HCV infection up to 76 days of culture. We demonstrated that the acute phase of HCV infection is characterized by the elevated levels of reactive oxygen species (ROS) associated in part with an increase of NADPH-oxidase transcripts and activity and a depletion of GSH accompanied by high rates of viral replication and apoptotic cell death. Conversely, the chronic phase is characterized by a reestablishment of reduced environment due to a decreased ROS production and increased GSH content in infected cells that might concur to the establishment of viral persistence. Treatment with the prooxidant auranofin of the persistently infected cultures induced the increase of viral RNA titer, suggesting that a prooxidant state could favor the reactivation of HCV viral replication that in turn caused cell damage and death. Our results suggest that targeting the redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a promising option for contrasting HCV infection.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Anticoli

Amatore

Matarrese

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…The reason for the contrasting effects of the two viruses appears to be due to their different effects on Nrf2, which in turn positively regulates ALR expression. Hepatitis C virus has been shown to have an inhibitory effect on Nrf2, whereas HBV positively regulates it . This is reflected in the findings in which HBV upregulates ALR but HCV does not.…”

Section: Viral Infection and Alrmentioning

confidence: 99%

Augmenter of liver regeneration: A key protein in liver regeneration and pathophysiology

Gupta

Venugopal

2018

Hepatology Research

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Liver is constantly exposed to pathogens, viruses, chemicals, and toxins, and several of them cause injury, leading to the loss of liver mass and sometimes resulting in cirrhosis and cancer. Under physiological conditions, liver can regenerate if the loss of cells is less than the proliferation of hepatocytes. If the loss is more than the proliferation, the radical treatment available is liver transplantation. Due to this reason, the search for an alternative therapeutic agent has been the focus of liver research. Liver regeneration is regulated by several growth factors; one of the key factors is augmenter of liver regeneration (ALR). Involvement of ALR has been reported in crucial processes such as oxidative phosphorylation, maintenance of mitochondria and mitochondrial biogenesis, and regulation of autophagy and cell proliferation. Augmenter of liver regeneration has been observed to be involved in liver regeneration by not only overcoming cell cycle inhibition but by maintaining the stem cell pool as well. These observations have created curiosity regarding the possible role of ALR in maintenance of liver health. Thus, this review brings a concise presentation of the work done in areas exploring the role of ALR in normal liver physiology and in liver health maintenance by fighting liver diseases, such as liver failure, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, viral infections, cirrhosis, and hepatocellular carcinoma.

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“…However, it is hard to illustrate this issue because both alcohol and HCV infection could induce autophagy in liver cells. Previous studies indicated that alcohol-induced oxidative stress or ER (endoplasmic reticulum) stress, both of which are known to be linked to autophagy activation 38 , are also involved in HCV-induced autophagy 39,40 . Thus, we expected that we could find some new intermediate host factors that are involved in alcohol-induced autophagy but do not derive from HCV infection, to explore the role of alcohol-induced autophagy in HCV replication and the mechanism(s) involved.…”

Section: Discussionmentioning

confidence: 99%

Alcohol-induced autophagy via upregulation of PIASy promotes HCV replication in human hepatoma cells

et al. 2018

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Both alcohol and hepatitis C virus (HCV) infection could induce cellular autophagy in liver cells, which is considered to be essential for productive HCV replication. However, whether alcohol-induced autophagy is involved in the pathogenesis of HCV infection is still poorly understood. Alcohol treatment could induce autophagy in Huh7 cells (a hepatoma cell line that supports HCV JFH-1 replication), evidenced by the increase of LC3B-II levels, the conversion of LC3B-I to LC3B-II, and the formation of GFP-LC3 puncta as well as the decrease of p62 level in alcohol-treated cells compared with control cells. Alcohol treatment also significantly increased PIASy (a member of the PIAS family) expression, which can act as a SUMO (small ubiquitin-like modifier protein) E3 ligase to regulate a broader range of cellular processes including autophagy. Overexpression or the silencing expression of PIASy in alcohol-treated Huh7 cells could increase or decrease autophagic activation caused by alcohol treatment, respectively, and thus affect HCV replication correspondingly. In the absence of alcohol, overexpression or silencing expression of PIASy increase or decrease the level of cellular autophagy, judged by the changes of LC3B-II and p62 levels in the presence or absence of chloroquine (CQ), a lysosome inhibitor. More importantly, in the presence of 3-methyladenine (3-MA), an inhibitor in the early stage of autophagy, the effects of overexpression or silencing expression of PIASy on HCV replication were largely blocked. Furthermore, PIASy could selectively drive the accumulation of SUMO1-conjugated proteins, along with upregulation of the expression of several important autophagy factors, including ATG7 and ATG5–ATG12. In conclusion, alcohol promotes HCV replication through activation of autophagy in Huh7 cells, which partly attributes to its induction of PIASy expression. PIASy-enhanced accumulation of SUMO1-conjugated proteins may contribute to its inducing effect of autophagy. Our findings provide a novel mechanism for the action of alcohol-promoting HCV replication in the context of cellular autophagy.

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HCV-induced oxidative stress by inhibition of Nrf2 triggers autophagy and favors release of viral particles

Cited by 55 publications

References 67 publications

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Augmenter of liver regeneration: A key protein in liver regeneration and pathophysiology

Alcohol-induced autophagy via upregulation of PIASy promotes HCV replication in human hepatoma cells

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