Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates

Sabile, Abdelmajid; Perlemuter, Gabriel; Bono, Fulvia; Kohara, Kyoko; Kohara, Michinori; Matsuura, Yoshiharu; Miyamura, Tatsuo; Bréchot, Christian; Barba, Giovanna

doi:10.1002/hep.510300429

Cited by 160 publications

(126 citation statements)

References 67 publications

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“…We analysed the sub-cellular localisation of core and PKR. Core showed a cytoplasmic localisation consistent with that previously reported in di erent cell lines (Barba et al, 1997;Sabile et al, 1999;Yasui et al, 1998). Confocal analysis revealed co-localization, in the presence or absence of IFNa treatment (data not shown), of cores expressed from the tumor-derived sequences (AT1, BT1 and BT2), and not the non tumor-derived sequences-(ANT1, ANT2 and BNT1), and PKR (Figure 2a).…”

Section: Resultssupporting

confidence: 90%

“…Several studies have in particular established that HCV core, a 191 amino acid basic protein with RNA binding activity, regulates important cellular signals, such as those which control NF-kB-, AP 1-and SRE-activities, MAP kinases, raf, P53 and P21 (Lai and Ware, 2000;Marusawa et al, 1999;Otsuka et al, 2000;Tsuchihara et al, 1999). HCV core has been described as being associated with lymphotoxin-b receptor, TNF-receptor 1, apolipoprotein AII, hnRNP and a bZIP transcription factor (Barba et al, 1997;Chen et al, 1997;Hsieh et al, 1998;Sabile et al, 1999). Evidence exists that HCV core may have an e ect upon cell transformation (Jin et al, 2000) and apoptosis (Marusawa et al, 1999;Ray et al, 1996Ray et al, , 1998Ruggieri et al, 1997); however, the biological consequences of core ectopic expression depend on the levels of expression achieved, the cell type utilized and the cellular environment (Honda et al, 2000;Zhu et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Activation of the interferon-inducible protein kinase PKR by Hepatocellular carcinoma derived-Hepatitis C virus core protein

et al. 2001

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Hepatitis C virus (HCV) is a major etiological agent of chronic liver disease and hepatocellular carcinoma (HCC). We demonstrate herewith that HCV core proteins encoded by sequences isolated from HCC tumor tissues, but not those derived from their non-tumor counterparts in the same liver, co-localise in vitro and in vivo and co-immunoprecipitate with PKR in hepatocytic Huh7 cells. We show that this association in fact augments the autophosphorylation of PKR and the phosphorylation of the translation initiation factor eIF2a, which are two markers of PKR activity. The present study therefore identi®es a novel model of viruscell interactions whereby a viral protein, the HCV core, activates PKR activity. Oncogene (2001) 20, 5836 ± 5845.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Activation of the interferon-inducible protein kinase PKR by Hepatocellular carcinoma derived-Hepatitis C virus core protein

et al. 2001

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“…These in vitro studies, occurring in genotype-1-derived constructs, have suggested that these proteins may interact directly with cytoplasmic lipid structures, specifically apoA1 and apoA2, altering lipid metabolism. 6,7 Inhibition of microsomal triglyceride transfer protein also has been shown, resulting in impaired fat trafficking. 8 This finding is supported in human studies showing decreased apoB levels, a component of very low-density lipoprotein, in patients with significant hepatic steatosis.…”

Section: Steatosis Mediated Via Hepatitis C Virusmentioning

confidence: 99%

Steatosis and Chronic Hepatitis C Infection: Mechanisms and Significance

Harrison

2005

Clinical Gastroenterology and Hepatology

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“…In addition to forming the viral nucleocapsids, core protein affects a whole array of host cell functions, including apoptosis, cell transformation, signal transduction, and transcriptional regulation (reviewed in references 73 and 78). In addition to cytoplasmic and nuclear localization, the HCV core protein is also secreted from stably transfected cells and has been found in the bloodstream of infected individuals, where it may provide an infection-inde-pendent mechanism of immune dysregulation (31,62). Coreinduced immune dysregulation includes suppression of Th1 polarization, inhibition of IFN-␥-mediated cytotoxic T-lymphocyte (CTL) activation, and decreased interleukin-2 (IL-2) and IL-12 production (for a review, see reference 61).…”

mentioning

confidence: 99%

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

Ciccaglione

Stellacci

Marcantonio

et al. 2007

J Virol

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Hepatitis C virus (HCV) proteins are known to interfere at several levels with both innate and adaptive responses of the host. A key target in these effects is the interferon (IFN) signaling pathway. While the effects of nonstructural proteins are well established, the role of structural proteins remains controversial. We investigated the effect of HCV structural proteins on the expression of interferon regulatory factor 1 (IRF-1), a secondary transcription factor of the IFN system responsible for inducing several key antiviral and immunomodulatory genes. We found substantial inhibition of IRF-1 expression in cells expressing the entire HCV replicon. Suppression of IRF-1 synthesis was mainly mediated by the core structural protein and occurred at the transcriptional level. The core protein in turn exerted a transcriptional repression of several interferonstimulated genes, targets of IRF-1, including interleukin-15 (IL-15), IL-12, and low-molecular-mass polypeptide 2. These data recapitulate in a unifying mechanism, i.e., repression of IRF-1 expression, many previously described pathogenetic effects of HCV core protein and suggest that HCV core-induced IRF-1 repression may play a pivotal role in establishing persistent infection by dampening an effective immune response.Infection with hepatitis C virus (HCV) represents the major cause of liver disease, affecting more than 170 million individuals worldwide (26). After a subclinical phase, more than 80% of patients progress to persistent HCV infection, which is the leading cause of chronic liver disease associated with cirrhosis and hepatocellular carcinoma (13). The persistence of the virus in the majority of infected individuals is linked to the ability of HCV to evade and/or antagonize the host immune response at both the local and systemic levels. Accordingly, although hepatocytes are a major target of HCV infection, the virus can also replicate in immune cells, including effector cells (1,11). In this respect, resistance to interferon (IFN) therapy is a hallmark of evolution in persistence, indicating that knocking down the antiviral and immunomodulating effects of IFN is a successful strategy for evading the host immune surveillance (21). The production and secretion of IFN type I is pivotal in inducing a global antiviral state through paracrine IFN production and the subsequent activation of interferon-stimulated genes (ISGs) within the infected cells and in the surrounding tissues (70). The role of IFN in HCV infection is thus crucial (21). Functional genomic analyses from cohorts of human subjects with chronic infection have shown that infection is associated with a gene expression profile marked by ISGs whose level of expression is related to different degrees of liver fibrosis and cirrhosis (67). Similarly, gene expression profiling has demonstrated that acute resolving infections in chimpanzees are associated with high levels of hepatic ISG expression (4).The single-stranded RNA genome of HCV is translated into a polypeptide precursor of 3,010 amino aci...

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Hepatitis C virus core protein binds to apolipoprotein AII and its secretion is modulated by fibrates

Cited by 160 publications

References 67 publications

Activation of the interferon-inducible protein kinase PKR by Hepatocellular carcinoma derived-Hepatitis C virus core protein

Activation of the interferon-inducible protein kinase PKR by Hepatocellular carcinoma derived-Hepatitis C virus core protein

Steatosis and Chronic Hepatitis C Infection: Mechanisms and Significance

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

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