Hepatitis C virus internal ribosome entry site‐mediated translation is stimulated by <i>cis</i>‐acting RNA elements and <i>trans</i>‐acting viral factors

Lourenco, Sofia; Costa, Fleur; Débarges, Béatrice; Andrieu, Thibault; Cahour, Annie

doi:10.1111/j.1742-4658.2008.06566.x

Cited by 26 publications

(27 citation statements)

References 69 publications

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“…4C suggests that the kissing-loop interaction may be conserved between 5BSL3.2 and the 3=SL II of the EHcV genome through their complementary sequences. The long-range RNA-RNA interaction between the apical loop of subdomain IIId in HCV IRES and the bulge of 5BSL3.2 supports IRES-dependent translation and viral RNA replication (34)(35)(36). In the case of the EHcV genome, the complement sequences were detected in the apical loops of subdomain and the 5BSL3.2-like subdomain (Fig.…”

Section: Detection Of the Ehcv Genome And Antibody To Ehcv In Sera Ofmentioning

confidence: 93%

Hallmarks of Hepatitis C Virus in Equine Hepacivirus

Tanaka

Kasai

Yamashita

et al. 2014

J Virol

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Equine hepacivirus (EHcV) has been identified as a closely related homologue of hepatitis C virus (HCV) in the United States, the United Kingdom, and Germany, but not in Asian countries. In this study, we genetically and serologically screened 31 serum samples obtained from Japanese-born domestic horses for EHcV infection and subsequently identified 11 PCR-positive and 7 seropositive serum samples. We determined the full sequence of the EHcV genome, including the 3= untranslated region (UTR), which had previously not been completely revealed IMPORTANCEEHcV, which shows the highest amino acid or nucleotide homology to HCV among hepaciviruses, was previously reported to infect horses from Western, but not Asian, countries. We herein report EHcV infection in Japanese-born horses. In this study, HCV-like RNA secondary structures around both UTRs were predicted by determining the whole-genome sequence of EHcV. Our results also suggest that the EHcV core protein is cleaved by SPP to become a mature form and then is localized on lipid droplets and partially on lipid raft-like membranes in a manner similar to that of the HCV core protein. Hence, EHcV was identified as a closely related homologue of HCV based on its genetic structure as well as its biological properties. A clearer understanding of the epidemiology, genetic structure, and infection mechanism of EHcV will assist in elucidating the evolution of hepaciviruses as well as the development of surrogate models for the study of HCV.

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Section: Detection Of the Ehcv Genome And Antibody To Ehcv In Sera Ofmentioning

confidence: 93%

Hallmarks of Hepatitis C Virus in Equine Hepacivirus

Tanaka

Kasai

Yamashita

et al. 2014

J Virol

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“…Transition between these processes is complex and requires strict control that needs to integrate multiple functional elements. The interaction involving domains IIId and 5BSL3.2, together with other viral factors previously proposed (Domitrovich et al 2005;Lourenco et al 2008), might be involved in this regulation.…”

Section: Discussionmentioning

confidence: 99%

“…This is the case of flavivirus , certain picornaviruses, such as FMDV (Serrano et al 2006), retroviruses (Ooms et al 2007;Kenyon et al 2008), or Dengue virus (Polacek et al 2009), among others. With respect to HCV, conflicting results regarding the role of the 39 UTR in viral protein synthesis have been reported (Ito et al 1998;Ito and Lai 1999;Fang and Moyer 2000;Michel et al 2001;Murakami et al 2001;Kong and Sarnow 2002;McCaffrey et al 2002;Imbert et al 2003;Bradrick et al 2006;Song et al 2006;Lourenco et al 2008). Today it is commonly accepted that the 39 end exerts an enhancer translational effect through the recruitment of viral and cellular protein factors that stimulate IRES activity (McCaffrey et al 2002;Bradrick et al 2006;Song et al 2006;Lourenco et al 2008).…”

Section: Introductionmentioning

confidence: 99%

A long-range RNA–RNA interaction between the 5′ and 3′ ends of the HCV genome

Romero-López¹,

Berzal‐Herranz²

2009

RNA

112

146

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The RNA genome of the hepatitis C virus (HCV) contains multiple conserved structural cis domains that direct protein synthesis, replication, and infectivity. The untranslatable regions (UTRs) play essential roles in the HCV cycle. Uncapped viral RNAs are translated via an internal ribosome entry site (IRES) located at the 59 UTR, which acts as a scaffold for recruiting multiple protein factors. Replication of the viral genome is initiated at the 39 UTR. Bioinformatics methods have identified other structural RNA elements thought to be involved in the HCV cycle. The 5BSL3.2 motif, which is embedded in a cruciform structure at the 39 end of the NS5B coding sequence, contributes to the three-dimensional folding of the entire 39 end of the genome. It is essential in the initiation of replication. This paper reports the identification of a novel, strand-specific, long-range RNA-RNA interaction between the 59 and 39 ends of the genome, which involves 5BSL3.2 and IRES motifs. Mutants harboring substitutions in the apical loop of domain IIId or in the internal loop of 5BSL3.2 disrupt the complex, indicating these regions are essential in initiating the kissing interaction. No complex was formed when the UTRs of the related foot and mouth disease virus were used in binding assays, suggesting this interaction is specific for HCV sequences. The present data firmly suggest the existence of a higher-order structure that may mediate a protein-independent circularization of the HCV genome. The 59-39 end bridge may have a role in viral translation modulation and in the switch from protein synthesis to RNA replication.

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“…This result further supported that MAPKAPK3 modulated the HCV protein level but not the intracellular HCV RNA level. Since HCV IRES-mediated translation was specifically modulated by HCV core protein in previous studies (23,24) and knockdown of MAPKAPK3 significantly decreased HCV IRES activity in the presence of core protein in the current study, these data indicated that modulation of HCV IRES-mediated translation by core protein occurred through MAPKAPK3 protein. Moreover, overexpression of mutant core containing the necessary region to bind to MAPKAPK3 competed away the protein interaction between wild-type core and MAPKAPK3, and hence HCV IRES activity was impaired.…”

Section: Discussionmentioning

confidence: 71%

“…These data indicate that MAPKAPK3 is involved in HCV IRES-mediated translation. It has been previously reported that HCV core stimulated HCV IRES activity (23,24). Indeed, overexpression of core protein increased HCV IRES activity 1.5-fold compared to vector control, and core-mediated IRES activity was further elevated by MAPKAPK3 in a dose-dependent manner (Fig.…”

Section: Identification Of Cellular Proteins Interacting With Hcv Cormentioning

confidence: 69%

Modulation of Mitogen-Activated Protein Kinase-Activated Protein Kinase 3 by Hepatitis C Virus Core Protein

Ngo

Pham

Kim

et al. 2013

J Virol

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Hepatitis C virus (HCV) is highly dependent on cellular proteins for its own propagation. In order to identify the cellular factors involved in HCV propagation, we performed protein microarray assays using the HCV core protein as a probe. Of ϳ9,000 host proteins immobilized in a microarray, approximately 100 cellular proteins were identified as HCV core-interacting partners. Of these candidates, mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3) was selected for further characterization. MAPKAPK3 is a serine/threonine protein kinase that is activated by stress and growth inducers. Binding of HCV core to MAPKAPK3 was confirmed by in vitro pulldown assay and further verified by coimmunoprecipitation assay. HCV core protein interacted with MAPKAPK3 through amino acid residues 41 to 75 of core and the N-terminal half of kinase domain of MAPKAPK3. In addition, both RNA and protein levels of MAPKAPK3 were elevated in both HCV subgenomic replicon cells and cell culture-derived HCV (HCVcc)-infected cells. Silencing of MAPKAPK3 expression resulted in decreases in both protein and HCV infectivity levels but not in the intracellular HCV RNA level. We showed that MAPKAPK3 increased HCV IRES-mediated translation and MAPKAPK3-dependent HCV IRES activity was further increased by core protein. These data suggest that HCV core may modulate MAPKAPK3 to facilitate its own propagation.

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Hepatitis C virus internal ribosome entry site‐mediated translation is stimulated by cis‐acting RNA elements and trans‐acting viral factors

Cited by 26 publications

References 69 publications

Hallmarks of Hepatitis C Virus in Equine Hepacivirus

Hallmarks of Hepatitis C Virus in Equine Hepacivirus

A long-range RNA–RNA interaction between the 5′ and 3′ ends of the HCV genome

Modulation of Mitogen-Activated Protein Kinase-Activated Protein Kinase 3 by Hepatitis C Virus Core Protein

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