Identification of proteins that mediate the pro-viral functions of the interferon stimulated gene 15 in hepatitis C virus replication

Real, CI; Megger, Dominik A.; Sitek, Barbara; Jahn‐Hofmann, Kerstin; Ickenstein, Ludger M.; John, Matthias; Walker, Andreas; Timm, Joerg; Kuhlmann, Katja; Eisenacher, Martin; Meyer, Helmut E.; Gerken, Guido; Broering, Ruth; Schlaak, Joerg F.

doi:10.1016/j.antiviral.2013.10.009

Cited by 21 publications

(20 citation statements)

References 45 publications

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“…Using a label‐free proteomic approach, seven host factors have recently been identified, which showed an ISG15‐dependent expression [heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3), heterogeneous nuclear ribonucleoprotein K (HNRNPK), hydroxymethylglutaryl‐CoA synthase (HMGCS1), isocitrate dehydrogenase cytoplasmic (IDH1), proteasome subunit alpha type‐6 (PSMA6), medium‐chain specific acyl‐CoA dehydrogenase (ACADM) and thioredoxin domain‐containing protein 5 (TXNDC5)]. All of these candidates are likely to be involved in HCV replication, affecting either lipid metabolism or translational control via RNA binding . Here, proteomic analyses have been performed with liver biopsies of HCV‐infected patients ( n = 27) and uninfected patients ( n = 10) to investigate hepatic expression of these host factors.…”

Section: Resultsmentioning

confidence: 99%

“…Comparison of PSMA6 and IFIT1 signals also resulted in linear correlation with R 2 = 0.2429 and P = 0.001, suggesting a connection between PSMA6 and ISG induction. An additional IDH1‐centred cluster of correlations further connected HMGCS1, HNRNPA3, HNRNPK and TXNDC5 ( R 2 and P values are given in Table S4), representing those five ISG15‐related candidates, which have been previously validated in the murine model .…”

Section: Resultsmentioning

confidence: 99%

“…To further investigate the effect of PSMA6 on either ISG15 expression or HCV replication, siRNA‐mediated knock‐down of PSMA6 and ISG15 mRNA levels was performed in highly replicative subgenomic replicon systems. The murine MH1 system has also been used in the initial study . Transfection was performed with 10 n m siRNA (siISG15 and siPSMA6); the nonsilencing control (siNC) was used at the maximum concentration of 20 n m .…”

Section: Resultsmentioning

confidence: 99%

“…We recently identified seven ISG15‐regulated proteins, which are either involved in lipid metabolism or harbour RNA‐binding capacities. Therefore, all of these proteins are likely to be associated with the HCV replication complex and possibly mediate the proviral ISG15 effect . In the present study correlations between these host factors, ISG15 and viral parameters were investigated.…”

Section: Introductionmentioning

confidence: 94%

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Hepatic expression of proteasome subunit alpha type‐6 is upregulated during viral hepatitis and putatively regulates the expression of ISG15 ubiquitin‐like modifier, a proviral host gene in hepatitis C virus infection

Broering

Trippler

Werner

et al. 2016

Journal of Viral Hepatitis

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The interferon-stimulated gene 15 (ISG15) plays an important role in the pathogenesis of hepatitis C virus (HCV) infection. ISG15-regulated proteins have previously been identified that putatively affect this proviral interaction. The present observational study aimed to elucidate the relation between ISG15 and these host factors during HCV infection. Transcriptomic and proteomic analyses were performed using liver samples of HCV-infected (n = 54) and uninfected (n = 10) or HBV-infected controls (n = 23). Primary human hepatocytes (PHH) were treated with Toll-like receptor ligands, interferons and kinase inhibitors. Expression of ISG15 and proteasome subunit alpha type-6 (PSMA6) was suppressed in subgenomic HCV replicon cell lines using specific siRNAs. Comparison of hepatic expression patterns revealed significantly increased signals for ISG15, IFIT1, HNRNPK and PSMA6 on the protein level as well as ISG15, IFIT1 and PSMA6 on the mRNA level in HCV-infected patients. In contrast to interferon-stimulated genes, PSMA6 expression occurred independent of HCV load and genotype. In PHH, the expression of ISG15 and PSMA6 was distinctly induced by poly(I:C), depending on IRF3 activation or PI3K/AKT signalling, respectively. Suppression of PSMA6 in HCV replicon cells led to significant induction of ISG15 expression, thus combined knock-down of both genes abrogated the antiviral effect induced by the separate suppression of ISG15. These data indicate that hepatic expression of PSMA6, which is upregulated during viral hepatitis, likely depends on TLR3 activation. PSMA6 affects the expression of immunoregulatory ISG15, a proviral factor in the pathogenesis of HCV infection. Therefore, the proteasome might be involved in the enigmatic interaction between ISG15 and HCV.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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Hepatic expression of proteasome subunit alpha type‐6 is upregulated during viral hepatitis and putatively regulates the expression of ISG15 ubiquitin‐like modifier, a proviral host gene in hepatitis C virus infection

Broering

Trippler

Werner

et al. 2016

Journal of Viral Hepatitis

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“…The protective mechanism of TXN can be attributed to its potent anti-oxidative and anti-inflammatory activities. TXN domaincontaining protein 5 is reportedly be associated with HCV replication (Real et al, 2013).…”

Section: Validation Of Proteomic Data By Western Blotmentioning

confidence: 99%

Proteomic Comparative Analysis of Pregnancy Serum Facilitating Hepatitis E Virus Replication in Hepatoma Cells

Li¹,

Bi²,

Wu³

et al. 2017

Preprint

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Activation of endogenous type I IFN signaling contributes to persistent HCV infection

Duan

et al. 2014

Reviews in Medical Virology

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HCV infection is a major world health problem, leading to both end-stage liver disease and primary liver cancer. Great efforts have been made in developing new therapies for HCV infection; however, combination therapy with pegylated IFN-α and ribavirin (pegIFN-RBV) remains the first choice of treatment for chronic HCV infection in most countries. The treatment response to pegIFN-RBV remains relatively low. Understanding the molecular mechanisms of persistent HCV infection and pegIFN-RBV resistance will suggest ways of improving the current standard of care and offers new antiviral therapies for both HCV and other viral infections. Recent data suggest that increased expression of hepatic IFN-stimulated genes (ISGs) before treatment is associated with treatment nonresponse in patients chronically infected with HCV. Although ISGs are generally antiviral in nature, in the case of HCV, the virus may exploit some of them to its benefit. This is not unique to HCV: Blockade of type I IFN signaling has been shown to control persistent LCMV infection. Thus, in certain viral infections, preactivation or overactivation of type I IFN signaling may contribute to viral persistence. In this review, we briefly summarize the findings from high-throughput gene expression profiling from patients chronically infected with HCV, then focus on a novel ubiquitin-like signaling pathway (ISG15/USP18) and its potential role in HCV persistence. Finally, the role of activation of endogenous type I IFN signaling in persistent HCV infection will be discussed in the context of recent studies indicating that blocking IFN signaling controls persistent LCMV infection.

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Identification of proteins that mediate the pro-viral functions of the interferon stimulated gene 15 in hepatitis C virus replication

Cited by 21 publications

References 45 publications

Hepatic expression of proteasome subunit alpha type‐6 is upregulated during viral hepatitis and putatively regulates the expression of ISG15 ubiquitin‐like modifier, a proviral host gene in hepatitis C virus infection

Hepatic expression of proteasome subunit alpha type‐6 is upregulated during viral hepatitis and putatively regulates the expression of ISG15 ubiquitin‐like modifier, a proviral host gene in hepatitis C virus infection

Proteomic Comparative Analysis of Pregnancy Serum Facilitating Hepatitis E Virus Replication in Hepatoma Cells

Activation of endogenous type I IFN signaling contributes to persistent HCV infection

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