Regulation of hepatitis C virus translation initiation by iron: Role of eIF3 and La protein

Wang, Qiang; Liu, Yiping; An, Daizhi; Diao, Hongyan; Xu, Wei; He, Xiaoqing; Sun, Rubao; Li, Wei; Li, Lanjuan

doi:10.1016/j.virusres.2012.05.014

Cited by 18 publications

(23 citation statements)

References 26 publications

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“…Thus, inasmuch as hepcidin regulates intracellular iron, either through FPN or an alternative unknown hepatocyte-specific mechanism, our data agree with previous studies that have demonstrated increased HCV IRES function in iron-loaded cells. 1,2,33 Others were unable to discern an association between iron and HCV translation, 34 but this discrepancy may be due to varied experimental conditions and cellular systems used. Furthermore, hepcidin overexpression resulted in significantly elevated HCV replication levels at 24 h -48 h p.t.…”

Section: Discussionmentioning

confidence: 99%

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

et al. 2016

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Mechanisms that favor Hepatitis C virus (HCV) persistence over clearance are unclear, but involve defective innate immunity. Chronic infection is characterized by hepatic iron overload, hyperferraemia and hyperferittinaemia. Hepcidin modulates iron egress via ferroportin and its storage in ferritin. Chronic HCV patients have decreased hepcidin, while HCV replication is modified by HAMP silencing. We aimed to investigate interactions between HCV and hepcidin, during acute and chronic disease, and putative alterations in cellular iron homeostasis that enhance HCV propagation and promote viral persistence. Thus, we used HCV JFH-1-infected co-cultures of Huh7.5 hepatoma and THP-1 macrophage cells, HCV patients' sera and Huh7 hepcidin-expressing cells transfected with HCV replicons. Hepcidin levels were elevated in acutely infected patients, but correlated with viral load in chronic patients. HAMP expression was up-regulated early in HCV infection in vitro, with corresponding changes in ferritin and FPN. Hepcidin overexpression enhanced both viral translation and replication. In HCV-infected co-cultures, we observed increased hepcidin, reduced hepatoma ferritin and a concurrent rise in macrophaghic ferritin over time. Altered iron levels complemented amplified replication in hepatoma cells and one replication round in macrophages. Iron-loading of macrophages led to enhancement of hepatic HCV replication through reversed ferritin "flow." Viral transmissibility from infected macrophages to na€ ıve hepatoma cells was induced by iron. We propose that HCV control over iron occurs both by intracellular iron sequestration, through hepcidin, and intercellular iron mobilisation via ferritin, as means toward enhanced replication. Persistence could be achieved through HCV-induced changes in macrophagic iron that enhances viral replication in these cells.

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Section: Discussionmentioning

confidence: 99%

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

et al. 2016

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“…Of interest is that these three JAK inhibitors reduce cellular La expression (Figure 3C and 3D) [45]. HAV and HCV modulate the JAK/STAT signaling pathway [50], [51].…”

Section: Discussionmentioning

confidence: 98%

“…It has been reported that down-regulation of La was induced by (-)-epigallocatechin gallate, iron chelator deferxamine and JAK inhibitor AZD1480 [43]–[45]. Ferric ammonium citrate up-regulates La expression [45].…”

Section: Discussionmentioning

confidence: 99%

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Suppression of La Antigen Exerts Potential Antiviral Effects against Hepatitis A Virus

Jiang

Nakamoto

et al. 2014

PLoS ONE

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BackgroundDespite the development and availability of hepatitis A virus (HAV) vaccine, HAV infection is still a major cause of acute hepatitis that occasionally leads to fatal liver disease. HAV internal ribosomal entry-site (IRES) is one of the attractive targets of antiviral agents against HAV. The aim of the present study is to evaluate the impact of La, one of the cellular proteins, on HAV IRES-mediated translation and HAV replication.Methods and FindingsWe investigated the therapeutic feasibility of siRNAs specific for cellular cofactors for HAV IRES-mediated translation in cell culture. It was revealed that siRNA against La could inhibit HAV IRES activities as well as HAV subgenomic replication. We also found that the Janus kinase (JAK) inhibitors SD-1029 and AG490, which reduce La expression, could inhibit HAV IRES activities as well as HAV replication.ConclusionsInhibition of La by siRNAs and chemical agents could lead to the efficient inhibition of HAV IRES-mediated translation and HAV replication in cell culture models. La might play important roles in HAV replication and is being exploited as one of the therapeutic targets of host-targeting antivirals.

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“…[16171819] Most of the studies suggest the positive role of iron on HCV translation. [20212223] To summarize the interactions between HCV and iron, and understand the mechanisms of iron overload in CHC, we searched articles published in the PubMed databases up to January 28, 2017, to gain an in-depth understanding and knowledge of relevant areas.…”

Section: Introductionmentioning

confidence: 99%

Relationship between Hepatitis C Virus Infection and Iron Overload

Zou

Sun

2017

Chinese Medical Journal

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Objective:The aim of this study was to summarize the interactions between hepatitis C virus (HCV) infection and iron overload, and to understand the mechanisms of iron overload in chronic hepatitis C (CHC) and the role iron plays in HCV life cycle.Data Sources:This review was based on data in articles published in the PubMed databases up to January 28, 2017, with the keywords “hepatitis C virus”, “iron overload”, “iron metabolism”, “hepcidin”, “translation”, and “replication”.Study Selection:Articles related to iron metabolism, iron overload in patients with CHC, or the effects of iron on HCV life cycle were selected for the review.Results:Iron overload is common in patients with CHC. The mechanisms involve decreased hepcidin levels caused by HCV through signal transducer and activator of transcription 3, mitogen-activated protein kinase, or bone morphogenetic protein/SMAD signaling pathways, and the altered expression of other iron-metabolism-related genes. Some studies found that iron increases HCV replication, while other studies found the opposite result. Most of the studies suggest the positive role of iron on HCV translation, the mechanisms of which involve increased expression levels of factors associated with HCV internal ribosome entry site-dependent translation, such as eukaryotic initiation factor 3 and La protein.Conclusion:The growing literature demonstrates that CHC leads to iron overload, and iron affects the HCV life cycle in turn. Further research should be conducted to clarify the mechanism involved in the complicated interaction between iron and HCV.

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Regulation of hepatitis C virus translation initiation by iron: Role of eIF3 and La protein

Cited by 18 publications

References 26 publications

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

Alterations in the iron homeostasis network: A driving force for macrophage-mediated hepatitis C virus persistency

Suppression of La Antigen Exerts Potential Antiviral Effects against Hepatitis A Virus

Relationship between Hepatitis C Virus Infection and Iron Overload

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