Hepatitis C Virus NS5A Binds to the mRNA Cap-binding Eukaryotic Translation Initiation 4F (eIF4F) Complex and Up-regulates Host Translation Initiation Machinery through eIF4E-binding Protein 1 Inactivation

George, Anju; Panda, Swarupa; Kudmulwar, Devika; Chhatbar, Salma Pathan; Nayak, Sanjeev Chavan; Krishnan, Harinivas H.

doi:10.1074/jbc.m111.308916

Cited by 46 publications

(41 citation statements)

References 75 publications

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“…These effects may contribute to the establishment of persistent HCV infection, since PI3K and mTOR inhibition enhances HCV replication (37). Recently, NS5A protein has been shown to bind to the mRNA cap-binding eukaryotic translation initiation 4F (eIF4F) complex and to upregulate host translation (38). (iv) Protein folding.…”

Section: Main Biological Processes Regulated By Hcv At the Translatiomentioning

confidence: 99%

Genome-Wide Analysis of Host mRNA Translation during Hepatitis C Virus Infection

Colman

Berre‐Scoul

Hernandez

et al. 2013

J Virol

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fIn the model of Huh-7.5.1 hepatocyte cells infected by the JFH1 hepatitis C virus (HCV) strain, transcriptomic and proteomic studies have revealed modulations of pathways governing mainly apoptosis and cell cycling. Differences between transcriptomic and proteomic studies pointed to regulations occurring at the posttranscriptional level, including the control of mRNA translation. In this study, we investigated at the genome-wide level the translational regulation occurring during HCV infection. Sucrose gradient ultracentrifugation followed by microarray analysis was used to identify translationally regulated mRNAs (mRNAs associated with ribosomes) from JFH1-infected and uninfected Huh-7.5.1 cells. Translationally regulated mRNAs were found to correspond to genes enriched in specific pathways, including vesicular transport and posttranscriptional regulation. Interestingly, the strongest translational regulation was found for mRNAs encoding proteins involved in pre-mRNA splicing, mRNA translation, and protein folding. Strikingly, these pathways were not previously identified, through transcriptomic studies, as being modulated following HCV infection. Importantly, the observed changes in host mRNA translation were directly due to HCV replication rather than to HCV entry, since they were not observed in JFH1-infected Huh-7.5.1 cells treated with a potent HCV NS3 protease inhibitor. Overall, this study highlights the need to consider, beyond transcriptomic or proteomic studies, the modulation of host mRNA translation as an important aspect of HCV infection.

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Section: Main Biological Processes Regulated By Hcv At the Translatiomentioning

confidence: 99%

Genome-Wide Analysis of Host mRNA Translation during Hepatitis C Virus Infection

Colman

Berre‐Scoul

Hernandez

et al. 2013

J Virol

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“…It has been shown by George et al 33 that HCV NS5A itself is able to activate mTORC1, which upregulates cap-dependent host protein translation and development of HCV-associated hepatocellular carcinoma. However, a direct link to viral replication and translation was not part of this study.…”

Section: Discussionmentioning

confidence: 99%

Host cell mTORC1 is required for HCV RNA replication

Stöhr

Costa

Sandmann

et al. 2015

Gut

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ObjectiveChronically HCV-infected orthotopic liver transplantation (OLT) recipients appear to have improved outcomes when their immunosuppressive regimen includes a mammalian target of rapamycin (mTOR) inhibitor. The mechanism underlying this observation is unknown.DesignWe used virological assays to investigate mTOR signalling on the HCV replication cycle. Furthermore, we analysed HCV RNA levels of 42 HCV-positive transplanted patients treated with an mTOR inhibitor as part of their immunosuppressive regimen.ResultsThe mTOR inhibitor rapamycin was found to be a potent inhibitor for HCV RNA replication in Huh-7.5 cells as well as primary human hepatocytes. Half-maximal inhibition was observed at 0.01 µg/mL, a concentration that is in the range of serum levels seen in transplant recipients and does not affect cell proliferation. Early replication cycle steps such as cell entry and RNA translation were not affected. Knockdown of raptor, an essential component of mTORC1, but not rictor, an essential component of mTORC2, inhibited viral RNA replication. In addition, overexpression of raptor led to higher viral RNA replication, demonstrating that mTORC1, but not mTORC2, is required for HCV RNA replication. In 42 HCV-infected liver-transplanted or kidney-transplanted patients who were switched to an mTOR inhibitor, we could verify that mTOR inhibition decreased HCV RNA levels in vivo.ConclusionsOur data identify mTORC1 as a novel HCV replication factor. These findings suggest an underlying mechanism for the observed benefits of mTOR inhibition in HCV-positive OLT recipients and potentiate further investigation of mTOR-containing regimens in HCV-positive recipients of solid organ transplants.

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“…For example, p38 MAPK activation and signaling is important for viral entry of reovirus and respiratory virus (Huang et al, 2011; Marchant et al, 2010). p38 MAPK signaling has also been implicated as playing a role in the viral transcription and translation of a number of viruses including hepatitis C virus, avian reovirus, porcine circovirus type 2, porcine reproductive and respiratory syndrome virus, rotavirus, Kaposi sarcoma-associated herpesvirus, encephalomyocarditis virus and HIV-1 (Cohen et al, 1997; George et al, 2012; Hirasawa et al, 2003; Jafri et al, 2007; Ji et al, 2009; Lee and Lee, 2012; Pan et al, 2006; Wei et al, 2009); and inhibition of p38 MAPK signaling has been shown to directly inhibit virus infection (Chang et al, 2008; Ludwig et al, 2003; Wei et al, 2009). EBOV infection induces MAPK signaling cascades in a GP-dependent manner, and p38 MAPK is thought to play dual roles in DC maturation and induction of inflammatory cytokines (Ayala et al, 2000; Lee et al, 2009; Terrazas et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells

et al. 2014

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Antigen presenting cells (APCs), including macrophages and dendritic cells, are early and sustained targets of Ebola virus (EBOV) infection in vivo. Because EBOV activates mitogen-activated protein kinase (MAPK) signaling upon infection of APCs, we evaluated the effect of pyridinyl imidazole inhibitors of p38 MAPK on EBOV infection of human APCs and EBOV mediated cytokine production from human DCs. The p38 MAPK inhibitors reduced viral replication in PMA-differentiated macrophage-like human THP-1 cells with an IC50 of 4.73μM (SB202190), 8.26μM (p38kinhIII) and 8.21μM (SB203580) and primary human monocyte-derived dendritic cells (MDDCs) with an IC50 of 2.67μM (SB202190). Furthermore, cytokine production from EBOV-treated MDDCs was inhibited in a dose-dependent manner. A control pyridinyl imidazole compound failed to inhibit either EBOV infection or cytokine induction. Using an established EBOV virus-like particle (VLP) entry assay, we demonstrate that inhibitor pretreatment blocked VLP entry suggesting that the inhibitors blocked infection and replication at least in part by blocking EBOV entry. Taken together, our results indicate that pyridinyl imidazole p38 MAPK inhibitors may serve as leads for the development of therapeutics to treat EBOV infection.

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Hepatitis C Virus NS5A Binds to the mRNA Cap-binding Eukaryotic Translation Initiation 4F (eIF4F) Complex and Up-regulates Host Translation Initiation Machinery through eIF4E-binding Protein 1 Inactivation

Cited by 46 publications

References 75 publications

Genome-Wide Analysis of Host mRNA Translation during Hepatitis C Virus Infection

Genome-Wide Analysis of Host mRNA Translation during Hepatitis C Virus Infection

Host cell mTORC1 is required for HCV RNA replication

Pyridinyl imidazole inhibitors of p38 MAP kinase impair viral entry and reduce cytokine induction by Zaire ebolavirus in human dendritic cells

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