scholarly journals Hepatitis C Virus Core Protein Associates with Detergent-Resistant Membranes Distinct from Classical Plasma Membrane Rafts

2004 ◽  
Vol 78 (21) ◽  
pp. 12047-12053 ◽  
Author(s):  
Meirav Matto ◽  
Charles M. Rice ◽  
Benjamin Aroeti ◽  
Jeffrey S. Glenn
Keyword(s):  
Plasma Membrane ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Biology ◽  
Core Protein ◽  
Nonstructural Protein ◽  
Virus Core ◽  
Hcv Core Protein ◽  
Classical Plasma ◽  
Detergent Resistant Membranes

ABSTRACT A subpopulation of hepatitis C virus (HCV) core protein in cells harboring full-length HCV replicons is biochemically associated with detergent-resistant membranes (DRMs) in a manner similar to that of markers of classical lipid rafts. Core protein does not, however, colocalize in immunofluorescence studies with classical plasma membrane raft markers, such as caveolin-1 and the B subunit of cholera toxin, suggesting that core protein is bound to cytoplasmic raft microdomains distinct from caveolin-based rafts. Furthermore, while both the structural core protein and the nonstructural protein NS5A associate with membranes, they do not colocalize in the DRMs. Finally, the ability of core protein to localize to the DRMs did not require other elements of the HCV polyprotein. These results may have broad implications for the HCV life cycle and suggest that the HCV core may be a valuable probe for host cell biology.

Structure and dynamics changes induced by 2,2,2-trifluoro-ethanol (TFE) on the N-terminal half of hepatitis C virus core proteinThis paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

2010 ◽  
Vol 88 (2) ◽  
pp. 315-323 ◽  
Author(s):  
Jean-Baptiste Duvignaud ◽  
Denis Leclerc ◽  
Stéphane M. Gagné
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Peer Review Process ◽  
Helical Structure ◽  
Functional Roles ◽  
Virus Core ◽  
Hcv Core Protein ◽  
Intrinsically Unstructured Protein ◽  
Unstructured Protein

The Core protein of hepatitis C virus is involved in several interactions other than the encapsidation of viral RNA. We recently proposed that this is related to the fact that the N-terminal half of this protein (C82) is an intrinsically unstructured protein (IUP) domain. IUP domains can adopt a secondary structure when they are interacting with another molecule, such as a nucleic acid or a protein. It is also possible to mimic these conditions by modifying the environment of the protein. We investigated the propensity of this protein to fold as a function of salt concentration, detergent, pH, and 2,2,2-trifluoro-ethanol (TFE); only the addition of TFE resulted in a structural change. The effect of TFE addition was studied by circular dichroism, structural, and dynamic data obtained by NMR. The data indicate that C82 can adopt an α-helical structure; this conformation is likely relevant to one of the functional roles of the HCV Core protein.

scholarly journals Hepatitis C Virus Core Protein Interacts with 14-3-3 Protein and Activates the Kinase Raf-1

2000 ◽  
Vol 74 (4) ◽  
pp. 1736-1741 ◽  
Author(s):  
Hiroshi Aoki ◽  
Junpei Hayashi ◽  
Mitsuhiko Moriyama ◽  
Yasuyuki Arakawa ◽  
Okio Hino
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Growth Regulation ◽  
Core Protein ◽  
Dependent Manner ◽  
Kinase Activation ◽  
Virus Core ◽  
Hcv Core Protein

ABSTRACT Persistent hepatitis C virus (HCV) infection is a major cause of chronic liver dysfunction in humans and is epidemiologically closely associated with the development of human hepatocellular carcinoma. Among HCV components, core protein has been reported to be implicated in cell growth regulation both in vitro and in vivo, although mechanisms explaining those effects are still unclear. In the present study, we identified that members of the 14-3-3 protein family associate with HCV core protein. 14-3-3 protein bound to HCV core protein in a phosphoserine-dependent manner. Introduction of HCV core protein caused a substantial increase in Raf-1 kinase activity in HepG2 cells and in a yeast genetic assay. Furthermore, the HCV core–14-3-3 interaction was essential for Raf-1 kinase activation by HCV core protein. These results suggest that HCV core protein may represent a novel type of Raf-1 kinase-activating protein through its interaction with 14-3-3 protein and may contribute to hepatocyte growth regulation.

scholarly journals Hepatitis C Virus Core Protein Blocks Interferon Signaling by Interaction with the STAT1 SH2 Domain

2006 ◽  
Vol 80 (18) ◽  
pp. 9226-9235 ◽  
Author(s):  
Wenyu Lin ◽  
Sun Suk Kim ◽  
Elaine Yeung ◽  
Yoshitaka Kamegaya ◽  
Jason T. Blackard ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Sh2 Domain ◽  
Type I ◽  
Interaction Domain ◽  
Virus Core ◽  
Hcv Core Protein ◽  
Signaling Components ◽  
Host Antiviral Response

ABSTRACT Emerging data have indicated that hepatitis C virus (HCV) subverts the host antiviral response to ensure its persistence. We previously demonstrated that HCV protein expression suppresses type I interferon (IFN) signaling by leading to the reduction of phosphorylated STAT1 (P-STAT1). We also demonstrated that HCV core protein directly bound to STAT1. However, the detailed mechanisms by which HCV core protein impacts IFN signaling components have not been fully clarified. In this report, we show that the STAT1 interaction domain resides in the N-terminal portion of HCV core (amino acids [aa] 1 to 23). This domain is also required to produce P-STAT1 reduction and inhibit IFN signaling transduction. Conversely, the C-terminal region of STAT1, specifically the SH2 domain (aa 577 to 684), is required for the interaction of HCV core with STAT1. The STAT1 SH2 domain is critical for STAT1 hetero- or homodimerization. We propose a model by which the binding of HCV core to STAT1 results in decreased P-STAT, blocked STAT1 heterodimerization to STAT2, and, therefore, reduced IFN-stimulated gene factor-3 binding to DNA and disrupted IFN-stimulated gene transcription.

scholarly journals Activation of STAT3 by the Hepatitis C Virus Core Protein Leads to Cellular Transformation

2002 ◽  
Vol 196 (5) ◽  
pp. 641-653 ◽  
Author(s):  
Takafumi Yoshida ◽  
Toshikatsu Hanada ◽  
Takeshi Tokuhisa ◽  
Ken-ichiro Kosai ◽  
Michio Sata ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Human Tumor ◽  
Cellular Transformation ◽  
Cytokine Signaling ◽  
Virus Core ◽  
Hcv Core Protein ◽  
Transformed Cell Lines ◽  
Nih 3T3

The signal transducer and activator of transcription (STAT) family proteins are transcription factors critical in mediating cytokine signaling. Among them, STAT3 is often constitutively phosphorylated and activated in human cancers and in transformed cell lines and is implicated in tumorigenesis. However, cause of the persistent activation of STAT3 in human tumor cells is largely unknown. The hepatitis C virus (HCV) is a major etiological agent of non-A and non-B hepatitis, and chronic infection by HCV is associated with development of liver cirrhosis and hepatocellular carcinoma. HCV core protein is proposed to be responsible for the virus-induced transformation. We now report that HCV core protein directly interacts with and activates STAT3 through phosphorylation of the critical tyrosine residue. Activation of STAT3 by the HCV core in NIH-3T3 cells resulted in rapid proliferation and up-regulation of Bcl-XL and cyclin-D1. Additional expression of STAT3 in HCV core-expressing cells resulted in anchorage-independent growth and tumorigenesis. We propose that the HCV core protein cooperates with STAT3, which leads to cellular transformation.

Up-regulation of FOXP3 and induction of suppressive function in CD4+ Jurkat T-cells expressing hepatitis C virus core protein

2012 ◽  
Vol 123 (1) ◽  
pp. 15-27 ◽  
Author(s):  
Margarita Dominguez-Villar ◽  
Cecilia Fernandez-Ponce ◽  
Alba Munoz-Suano ◽  
Esperanza Gomez ◽  
Manuel Rodríguez-Iglesias ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Cytotoxic T Lymphocyte ◽  
Treg Cells ◽  
Jurkat Cells ◽  
Jurkat T Cells ◽  
Virus Core ◽  
Hcv Core Protein

HCV (hepatitis C virus) infection is a serious health care problem that affects more than 170 million people worldwide. Viral clearance depends on the development of a successful cellular immune response against the virus. Interestingly, such a response is altered in chronically infected patients, leading to chronic hepatitis that can result in liver fibrosis, cirrhosis and hepatocellular carcinoma. Among the mechanisms that have been described as being responsible for the immune suppression caused by the virus, Treg-cells (regulatory T-cells) are emerging as an essential component. In the present work we aim to study the effect of HCV-core protein in the development of T-cells with regulatory-like function. Using a third-generation lentiviral system to express HCV-core in CD4+ Jurkat T-cells, we describe that HCV-core-expressing Jurkat cells show an up-regulation of FOXP3 (forkhead box P3) and CTLA-4 (cytotoxic T-lymphocyte antigen-4). Moreover, we show that HCV-core-transduced Jurkat cells are able to suppress CD4+ and CD8+ T-cell responses to anti-CD3 plus anti-CD28 stimulation.

scholarly journals Effects of hepatitis C virus core protein and nonstructural protein 4B on the Wnt/β-catenin pathway

2017 ◽  
Vol 17 (1) ◽  
Author(s):  
Xiao-Hua Jiang ◽  
Yu-Tao Xie ◽  
Ya-Ping Cai ◽  
Jing Ren ◽  
Tao Ma
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Protein ◽  
Nonstructural Protein ◽  
Virus Core

scholarly journals Sequence motifs required for lipid droplet association and protein stability are unique to the hepatitis C virus core protein

2000 ◽  
Vol 81 (8) ◽  
pp. 1913-1925 ◽  
Author(s):  
R. Graham Hope ◽  
John McLauchlan
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Lipid Droplets ◽  
Core Protein ◽  
Sequence Motifs ◽  
Primary Sequence ◽  
Unique Region ◽  
Virus Core ◽  
Hcv Core Protein ◽  
Intracellular Storage

From analysis of the primary sequence of the hepatitis C virus (HCV) core protein, we have identified three separable regions based on hydrophobicity and clustering of basic amino acids within the protein. Comparison with capsid proteins of related pesti- and flaviviruses suggested that HCV core has a unique central domain (domain 2). Previous findings have revealed that core protein can associate with lipid droplets which are intracellular storage sites for triacylglycerols and cholesterol esters. Confocal analysis of variant forms lacking regions of core indicated that most residues within the unique region are necessary for association of the protein with lipid droplets. A segment within domain 2 (from residues 125 to 144) also was required for stability of the protein and a polypeptide lacking these sequences was degraded apparently by the proteasome. In cells depleted of lipid droplets, core protein remained located in the cytoplasm. Moreover, cleavage of the protein at the maturation site and stability were not affected by inability to bind to lipid droplets.

scholarly journals Hepatitis C Virus Core Protein Augments Androgen Receptor-Mediated Signaling

2008 ◽  
Vol 82 (22) ◽  
pp. 11066-11072 ◽  
Author(s):  
Tatsuo Kanda ◽  
Robert Steele ◽  
Ranjit Ray ◽  
Ratna B. Ray
Keyword(s):  
Hepatitis C Virus ◽  
Androgen Receptor ◽  
Hepatitis C ◽  
Signaling Pathway ◽  
Core Protein ◽  
Tube Formation ◽  
Hcv Infection ◽  
Vegf Expression ◽  
Virus Core ◽  
Hcv Core Protein

ABSTRACT Hepatitis C virus (HCV) infection is frequently associated with the development of hepatocellular carcinoma (HCC), which is one of the male-dominant diseases. Androgen signaling in liver may be related to carcinogenesis. In this study, we investigated whether HCV proteins cross talk with the androgen receptor (AR) signaling pathway for promotion of carcinogenesis. We have demonstrated that HCV core protein alone or in context with other HCV proteins enhances AR-mediated transcriptional activity and further augments in the presence of androgen. Subsequent study suggested that HCV core protein activates STAT3, which in turn enhances AR-mediated transcription. This activity was blocked by a pharmacological inhibitor of the Jak/Stat signaling pathway, AG490. Vascular endothelial growth factor (VEGF) is a target gene of AR in liver and plays an important role in angiogenesis. Therefore, we examined whether HCV infection modulates VEGF expression in hepatocytes. Our results demonstrated that HCV enhances VEGF expression and facilitates tube formation in human coronary microvascular endothelial cells in the presence of AR. Together, our results suggest that HCV core protein acts as a positive regulator in AR signaling, providing further insight into oncogenic potential in the development of HCC in HCV-infected individuals.

scholarly journals Lack of expression of hepatitis C virus core protein in human monocyte-erived dendritic cells using recombinant semliki forest virus

2019 ◽  
Vol 24 (3) ◽  
pp. 493-502
Author(s):  
Maria-Cristina Navas ◽  
Françoise Stoll-Keller ◽  
Jovan Pavlovic
Keyword(s):  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Viral Vectors ◽  
Semliki Forest Virus ◽  
Core Protein ◽  
Human Monocyte ◽  
Host Immune System ◽  
Virus Core ◽  
Hcv Core Protein

Hepatitis C Virus belongs to the Flaviviridae family.  One proposed mechanism of HCV persistence in the ability to infect hematopoietic cells, including Dendritic cells (DCs). HCV infection of DCs could impair their functions that represent one of the mechanisms, thus hampering viral clearance by the host immune system. Among HCV-encoded proteins, the highly conserved Core protein has been suggested to be responsible for the immunomodulatory properties of this Hepacivirus. Recombinant viral vectors expressing the HCV Core protein and allowing its transduction and therefore the expression of the protein into DCs could be useful tools for the analysis of the properties of the Core protein. Vaccinia Virus and retrovirus have been used to transduce human DCs. Likewise, gene transfer into DCs using Semliki Forest Virus has been reported. This study aimed to express the HCV Core protein in human monocyte-derived DCs using an SFV vector, in which the subgenomic RNA encoding the structural proteins was replaced by the HCV Core sequence and then analyze the effects of its expression on DCs functions.

scholarly journals The Wild-Type Hepatitis C Virus Core Inhibits Initiation of Antigen-Specific T- and B-Cell Immune Responses in BALB/c Mice

2010 ◽  
Vol 17 (7) ◽  
pp. 1139-1147 ◽  
Author(s):  
Wenbo Zhu ◽  
Yanzi Chang ◽  
Chunchen Wu ◽  
Qingxia Han ◽  
Rongjuan Pei ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Responses ◽  
Core Protein ◽  
Repeated Administration ◽  
Wild Type ◽  
Virus Core ◽  
Hcv Core Protein ◽  
Core Proteins ◽  
Potential Applications

ABSTRACT In this study, the effects of wild-type and deletion mutant hepatitis C virus (HCV) core proteins on the induction of immune responses in BALB/c mice were assessed. p2HA-C145-S23, encoding a core protein with the C-terminal 46 amino acids truncated, significantly produced stronger antibody and cellular responses than p2HA-C191-S23. The induction of immune responses by p2HA-C145-S23 was dose dependent. However, increasing the doses or repeated administration did not enhance immune responses by the wild-type core protein. In addition, p2HA-C191-S23 was apparently able to interfere with the priming of specific immune responses by p2HA-C145-S23 when the two were coadministered. These results demonstrated that the wild-type HCV core protein itself could inhibit the priming of immune responses in the course of a DNA vaccination, whereas the truncated HCV core protein could provide potential applications for the development of DNA- and peptide-based HCV vaccines.

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