c-Fos regulates hepatitis C virus propagation

Kang, Sang Min; Lim, Seri; Won, Seung Jae; Shin, Ye Jin; Lim, Young Wook; Ahn, Byung Yoon; Hwang, Soon B.

doi:10.1016/j.febslet.2011.08.041

Cited by 17 publications

(14 citation statements)

References 33 publications

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“…9B) at 3% O 2 , together with oxidative stress-and ROS-related genes (see Table S2 in the supplemental material) that may contribute to oncogene induction. Among the induced oncogenes, FOS, MYC, SRC, and AKT have been already shown to directly activate glucose-related transporter and glycolytic gene promoters independently of HIFs (47,(57)(58)(59)(60)(61)(62) and, in addition, have been reported to stimulate HCV replication through either association with viral nonstructural proteins or other ways of action not completely defined (71,(79)(80)(81)(82)(83). In fact, our results confirmed the HIFindependent transcriptional activation of FOS and SRC (see Fig.…”

Section: Discussionsupporting

confidence: 80%

Low Oxygen Tension Enhances Hepatitis C Virus Replication

Vassilaki

Kalliampakou

Kotta‐Loizou

et al. 2013

J Virol

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; Applied Molecular Virology, Institut Pasteur Korea, Seongnam-si, South Korea g Low oxygen tension exerts a significant effect on the replication of several DNA and RNA viruses in cultured cells. In vitro propagation of hepatitis C virus (HCV) has thus far been studied under atmospheric oxygen levels despite the fact that the liver tissue microenvironment is hypoxic. In this study, we investigated the efficiency of HCV production in actively dividing or differentiating human hepatoma cells cultured under low or atmospheric oxygen tensions. By using both HCV replicons and infectionbased assays, low oxygen was found to enhance HCV RNA replication whereas virus entry and RNA translation were not affected. Hypoxia signaling pathway-focused DNA microarray and real-time quantitative reverse transcription-PCR (qRT-PCR) analyses revealed an upregulation of genes related to hypoxic stress, glycolytic metabolism, cell growth, and proliferation when cells were kept under low (3% [vol/vol]) oxygen tension, likely reflecting cell adaptation to anaerobic conditions. Interestingly, hypoxia-mediated enhancement of HCV replication correlated directly with the increase in anaerobic glycolysis and creatine kinase B (CKB) activity that leads to elevated ATP production. Surprisingly, activation of hypoxia-inducible factor alpha (HIF-␣) was not involved in the elevation of HCV replication. Instead, a number of oncogenes known to be associated with glycolysis were upregulated and evidence that these oncogenes contribute to hypoxia-mediated enhancement of HCV replication was obtained. Finally, in liver biopsy specimens of HCV-infected patients, the levels of hypoxia and anaerobic metabolism markers correlated with HCV RNA levels. These results provide new insights into the impact of oxygen tension on the intricate HCVhost cell interaction. H epatitis C virus (HCV) infection causes a wide range of clinical manifestations, from a healthy carrier state to acute and chronic hepatitis that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Nearly 3% of the world's population is chronically infected with HCV (1, 2), and current therapeutic approaches are not broadly effective (3).HCV is a positive-strand RNA virus with a 9.6-kb genome that is flanked at both termini by conserved, nontranslated regions (NTRs), required for RNA translation and replication. The 5= NTR comprises an internal ribosome entry site (IRES) that directs the expression of a polyprotein precursor (4, 5). The polyprotein is cleaved into structural (core, E1, E2) and nonstructural (p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B) proteins that, in association with cellular factors, form a membrane-associated replicase complex. This copies the viral positive-strand RNA into a negative-strand intermediate that serves as the template for the synthesis of progeny genomes. The alternative reading frame (ARFP) or coreϩ1 and minicore proteins, with as-yet-unknown functions, appear to be synthesized from the core region by alternative translation mechanisms (6, 7).Studies of the...

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Section: Discussionsupporting

confidence: 80%

Low Oxygen Tension Enhances Hepatitis C Virus Replication

Vassilaki

Kalliampakou

Kotta‐Loizou

et al. 2013

J Virol

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“…For dual luciferase reporter assay, Huh7.5 cells were transfected with 20 nM of the indicated siRNAs for 24 h and then transfected with pRL-HL plasmid together with beta-galactosidase plasmid, as we reported previously [11]. For HCV reporter assay, Huh7.5 cells were electroporated with 10 lg of in vitro transcribed JFHLuc RNA and treated with tylophorine for the indicated time points.…”

Section: Luciferase Replication Assaysmentioning

confidence: 99%

“…4A. Huh7.5 cells transfected with siRNAs were co-transfected with pRL-HL [11] and b-galactosidase plasmid, and then the luciferase activity was determined. We demonstrated that knockdown of CycA2 had no effect on HCV IRES-dependent translation (Fig.…”

Section: Cyca2 Is Involved In the Genome Replication Stage Of Hcv Lifmentioning

confidence: 99%

Hepatitis C virus non-structural 5B protein interacts with cyclin A2 and regulates viral propagation

Pham

Ngo

Lim

et al. 2012

Journal of Hepatology

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“…For the dual-luciferase reporter assay, Huh7.5 cells were transfected with 25 nM SCD1 siRNA or negative siRNA for 48 h and then transfected with pRL-HL plasmid and pCH110 reference plasmid as described previously (19). For the inhibitor assay, Huh7.5 cells transfected with the indicated plasmids were incubated with various dosages of SCD1 inhibitor.…”

Section: Methodsmentioning

confidence: 99%

Stearoyl Coenzyme A Desaturase 1 Is Associated with Hepatitis C Virus Replication Complex and Regulates Viral Replication

Nguyen

Lim

Pham

et al. 2014

J Virol

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The hepatitis C virus (HCV) life cycle is tightly regulated by lipid metabolism of host cells. In order to identify host factors involved in HCV propagation, we have recently screened a small interfering RNA (siRNA) library targeting host genes that control lipid metabolism and lipid droplet formation using cell culture-grown HCV (HCVcc)-infected cells. We selected and characterized the gene encoding stearoyl coenzyme A (CoA) desaturase 1 (SCD1). siRNA-mediated knockdown or pharmacological inhibition of SCD1 abrogated HCV replication in both subgenomic replicon and Jc1-infected cells, while exogenous supplementation of either oleate or palmitoleate, products of SCD1 activity, resurrected HCV replication in SCD1 knockdown cells. SCD1 was coimmunoprecipitated with HCV nonstructural proteins and colocalized with both double-stranded RNA (dsRNA) and HCV nonstructural proteins, indicating that SCD1 is associated with HCV replication complex. Moreover, SCD1 was fractionated and enriched with HCV nonstructural proteins at detergent-resistant membrane. Electron microscopy data showed that SCD1 is required for NS4B-mediated intracellular membrane rearrangement. These data further support the idea that SCD1 is associated with HCV replication complex and that its products may contribute to the proper formation and maintenance of membranous web structures in HCV replication complex. Collectively, these data suggest that manipulation of SCD1 activity may represent a novel host-targeted antiviral strategy for the treatment of HCV infection. IMPORTANCEStearoyl coenzyme A (CoA) desaturase 1 (SCD1), a liver-specific enzyme, regulates hepatitis C virus (HCV) replication through its enzyme activity. HCV nonstructural proteins are associated with SCD1 at detergent-resistant membranes, and SCD1 is enriched on the lipid raft by HCV infection. Therein, SCD1 supports NS4B-mediated membrane rearrangement to provide a suitable microenvironment for HCV replication. We demonstrated that either genetic or chemical knockdown of SCD1 abrogated HCV replication in both replicon cells and HCV-infected cells. These findings provide novel mechanistic insights into the roles of SCD1 in HCV replication. Hepatitis C virus (HCV) is an enveloped virus with a positivesense, single-stranded RNA virus that belongs to the genus Hepacivirus in the family Flaviviridae (1). Approximately 170 million people are chronically infected with HCV worldwide. Three million people are newly infected with HCV annually, and more than 350,000 individuals die from HCV-related liver diseases every year (1, 2). Current standard therapy elicits some side effects and results in a sustained virological response in only certain genotypes of HCV patients. Recently, the U.S. Food and Drug Administration approved various direct-acting antivirals (DAAs), including boceprevir, telaprevir, sofosbuvir, and simeprevir, for triple therapy in combination with pegylated interferon and ribavirin for patients with certain genotypes. Nevertheless, these new DAAs also have had some lim...

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c-Fos regulates hepatitis C virus propagation

Cited by 17 publications

References 33 publications

Low Oxygen Tension Enhances Hepatitis C Virus Replication

Low Oxygen Tension Enhances Hepatitis C Virus Replication

Hepatitis C virus non-structural 5B protein interacts with cyclin A2 and regulates viral propagation

Stearoyl Coenzyme A Desaturase 1 Is Associated with Hepatitis C Virus Replication Complex and Regulates Viral Replication

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