Farnesyl‐diphosphate farnesyltransferase 1 regulates hepatitis C virus propagation

Park, Eun-Mee; Nguyen, Lam; Lim, Yun-Sook; Hwang, Soon B.

doi:10.1016/j.febslet.2014.03.043

Cited by 15 publications

(16 citation statements)

References 30 publications

(40 reference statements)

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“…1) plays an important role in the HCV life cycle. This conclusion is consistent with recent studies showing that inhibition of oxidosqualene cyclase, lanosterol C 14 -demethylase, 24-dehydrocholesterol reductase, 7-dehydrocholesterol reductase, and SQS (discussed below) leads to decreased HCV production (31)(32)(33)62). Furthermore, we propose that SQS is a potential target for anti-HCV strategies because all the SQS inhibitors tested in this study exerted anti-HCV effects.…”

Section: Discussionsupporting

confidence: 93%

“…Our data provide evidence that the committed pathway of cholesterol biosynthesis is important for HCV production, consistent with recent studies (31)(32)(33)62). Moreover, we found that biosynthesis of cholesterol, but not of cholesteryl esters, is important for this process.…”

Section: Discussionsupporting

confidence: 93%

“…During preparation of this paper, Park et al reported that siRNAs against farnesyl-diphosphate farnesyltransferase 1 (another name for SQS) and YM-53601 impair propagation of the HCV Jc1 strain (genotype 2a) in Huh-7.5 cells (62). They suggested that these agents target viral RNA replication by using a luciferaseencoding full genomic replicon of the JFH-1 strain and genotype 2a subgenomic replicon cells.…”

Section: Discussionmentioning

confidence: 99%

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Targeting Cellular Squalene Synthase, an Enzyme Essential for Cholesterol Biosynthesis, Is a Potential Antiviral Strategy against Hepatitis C Virus

Saito

Shirasago

Suzuki

et al. 2015

J Virol

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Hepatitis C virus (HCV) exploits host membrane cholesterol and its metabolism for progeny virus production. Here, we examined the impact of targeting cellular squalene synthase (SQS), the first committed enzyme for cholesterol biosynthesis, on HCV production. By using the HCV JFH-1 strain and human hepatoma Huh-7.5.1-derived cells, we found that the SQS inhibitors YM-53601 and zaragozic acid A decreased viral RNA, protein, and progeny production in HCV-infected cells without affecting cell viability. Similarly, small interfering RNA (siRNA)-mediated knockdown of SQS led to significantly reduced HCV production, confirming the enzyme as an antiviral target. A metabolic labeling study demonstrated that YM-53601 suppressed the biosynthesis of cholesterol and cholesteryl esters at antiviral concentrations. Unlike YM-53601, the cholesterol esterification inhibitor Sandoz 58-035 did not exhibit an antiviral effect, suggesting that biosynthesis of cholesterol is more important than that of cholesteryl esters for HCV production. YM-53601 inhibited transient replication of a JFH-1 subgenomic replicon and entry of JFH-1 pseudoparticles, suggesting that at least suppression of viral RNA replication and entry contributes to the antiviral effect of the drug. Collectively, our findings highlight the importance of the cholesterol biosynthetic pathway in HCV production and implicate SQS as a potential target for antiviral strategies against HCV. IMPORTANCEHepatitis C virus (HCV) is known to be closely associated with host cholesterol and its metabolism throughout the viral life cycle. However, the impact of targeting cholesterol biosynthetic enzymes on HCV production is not fully understood. We found that squalene synthase, the first committed enzyme for cholesterol biosynthesis, is important for HCV production, and we propose this enzyme as a potential anti-HCV target. We provide evidence that synthesis of free cholesterol is more important than that of esterified cholesterol for HCV production, highlighting a marked free cholesterol dependency of HCV production. Our findings also offer a new insight into a role of the intracellular cholesterol pool that is coupled to its biosynthesis in the HCV life cycle.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting Cellular Squalene Synthase, an Enzyme Essential for Cholesterol Biosynthesis, Is a Potential Antiviral Strategy against Hepatitis C Virus

Saito

Shirasago

Suzuki

et al. 2015

J Virol

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“…By employing an siRNA library screening in HCVcc-infected cells, we have recently identified 10 host genes that might control lipid metabolism and lipid droplet formation (8). Of these, we selected SCD1 and investigated the functional involvement of SCD1 in HCV propagation.…”

Section: Scd1 Is Required For Hcv Replicationmentioning

confidence: 99%

“…Therefore, targeting host lipid metabolism could be an effective strategy to develop therapeutic agents for HCV-mediated liver diseases. Recently, we screened a small interfering RNA (siRNA) library targeting 114 genes that control lipid metabolism and lipid droplet formation in cell culture-grown HCV (HCVcc)-infected cells and identified 10 pools as candidate hits (8). In the present study, we selected stearoyl coenzyme A (CoA) desaturase 1 (SCD1) for further characterization.…”

mentioning

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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Gene expression profile after knockdown of USP18 in Hepg2.2.15 cells

et al. 2017

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In our previous work, we found that the expression of ubiquitin-specific protease 18 (USP18), also known as UBP43, is associated with the efficiency of interferon alpha (IFN-α) treatment in patients with chronic hepatitis B (CHB). To elucidate the influence of USP18 on hepatitis B virus (HBV) replication and the mechanism of this activity, we silenced USP18 by introducing short hairpin RNA (shRNA) into Hepg2.2.15 cells. To identify the changed genes and pathways in Hepg2.2.15-shRNA-USP18 cells, we performed a microarray gene expression analysis to compare the Hepg2.2.15 stably expressing USP18-shRNA cells versus control cells using the Affymetrix Human Transcriptome Array (HTA) 2.0 microarrays. Microarray analysis indicated that genes involved in regulation of thyroid hormone signaling pathway, complement, and coagulation cascades, PERK-mediated unfolded protein response, and insulin-like growth factor-activated receptor activity were significantly altered after USP18 knockdown for 72 h. Furthermore, genes involved in hepatocyte proliferation, liver fibrosis, such as cell cycle regulatory gene CCND1, were also altered after USP18 knockdown in Hepg2.2.15 cells. In conclusion, USP18 is critical for regulating the replication of HBV in Hepg2.2.15 cells, which suggest that USP18 may be a candidate target for HBV treatment.

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Farnesyl‐diphosphate farnesyltransferase 1 regulates hepatitis C virus propagation

Cited by 15 publications

References 30 publications

Targeting Cellular Squalene Synthase, an Enzyme Essential for Cholesterol Biosynthesis, Is a Potential Antiviral Strategy against Hepatitis C Virus

Targeting Cellular Squalene Synthase, an Enzyme Essential for Cholesterol Biosynthesis, Is a Potential Antiviral Strategy against Hepatitis C Virus

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

Gene expression profile after knockdown of USP18 in Hepg2.2.15 cells

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