Regulation of Hepatitis C Virus Replication by Interferon Regulatory Factor 1

Kanazawa, Nobuo; Kurosaki, Masayuki; Sakamoto, Naoya; Enomoto, Nobuyuki; Itsui, Yasuhiro; Yamashiro, Tsuyoshi; Tanabe, Yoko; Maekawa, Shinya; Nakagawa, Mina; Chen, Cheng‐Hsin; Kakinuma, Sei; Oshima, Shigeru; Nakamura, Toshio; Kato, Takanobu; Wakita, Takaji; Watanabe, Mamoru

doi:10.1128/jvi.78.18.9713-9720.2004

Cited by 83 publications

(64 citation statements)

References 49 publications

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“…The inhibition of IRF-1 expression and IRF-E/ISRE activity in cells expressing a subgenomic replicon of HCV was reported by Kanazawa and colleagues (30). However, in the system analyzed, no direct correlation was found between the viral RNA replication and IRF-1 repression.…”

Section: Discussionmentioning

confidence: 68%

“…Recently, IRF-1 has been implicated in HCV infection as a negative regulator of HCV subgenomic replicon (30). Using different experimental approaches, including cells expressing the entire HCV genomic replicon or cells conditionally or transiently expressing only the structural proteins, we show here that the expression of viral proteins, in particular of the HCV core protein, results in IRF-1 repression, which is reversed in IFN-cured cells.…”

mentioning

confidence: 78%

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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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Section: Discussionmentioning

confidence: 68%

mentioning

confidence: 78%

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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“…The various inhibitors were used at working concentration such as AG490 (50 lM), PD98059 (50 lM), SP600125 (25 lM), SB203580 (25 lM), LY294002 (25 lM) Rapamycin (6 nM), PP1 (2 lg/ml), Rottlerin (10 lM), Staurosporine (0.1 lM) and Genistein (10 lM). Mutated bases are underlined [16,17]. Locations are relative to the first translation start site.…”

Section: Rt-pcrmentioning

confidence: 99%

Interferon regulatory factor‐1 is prerequisite to the constitutive expression and IFN‐γ‐induced upregulation of B7‐H1 (CD274)

et al. 2006

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Majority of cancer cells upregulate co-inhibitory molecule B7-H1 which confers resistance to anti-tumor immunity, allowing cancers to escape from host immune surveillance. We addressed the molecular mechanism underlying the regulation of cancer-associated B7-H1 expression in response to interferon-c (IFN-c). Using promoter constructs in luciferase assay, the region between 202 and 320 bp from the translational start site is responsible for B7-H1 expression. Electrophoretic mobility shift assay, site-directed mutagenesis and knockdown experiment using siRNA revealed that interferon regulatory factor-1 (IRF-1) is primarily responsible for the constitutive B7-H1 expression as well as for the IFN-c-mediated B7-H1 upregulation in a human lung cancer cell line A549. Additionally, AG490, a Janus activated kinase/signal transducer and activator of transcription inhibitor, greatly abolished the responsiveness of A549 cells to IFN-c by reducing the IRF-1 transcription. Our findings support a critical role of IRF-1 in the regulation of constitutive and IFN-c-induced expression of B7-H1 in cancer cells.

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“…5). Among the mRNAs we analyzed here, IRF-1, MHC I, and ICAM-1, which have roles in antiviral response (41)(42)(43), were significantly retained in the nucleus of Nup98 or Rae1 mutant cells (Fig. 5), resulting in reduced cytoplasmic accumulation that may contribute to the increase in viral replication observed in some of these cells (Fig.…”

Section: Influenza Virus Virulence Correlates With Impaired Mrna Exportmentioning

confidence: 99%

Influenza virus targets the mRNA export machinery and the nuclear pore complex

Satterly

Tsai

Deursen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

253

274

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The NS1 protein of influenza A virus is a major virulence factor that is essential for pathogenesis. NS1 functions to impair innate and adaptive immunity by inhibiting host signal transduction and gene expression, but its mechanisms of action remain to be fully elucidated. We show here that NS1 forms an inhibitory complex with NXF1/TAP, p15/NXT, Rae1/mrnp41, and E1B-AP5, which are key constituents of the mRNA export machinery that interact with both mRNAs and nucleoporins to direct mRNAs through the nuclear pore complex. Increased levels of NXF1, p15, or Rae1 revert the mRNA export blockage induced by NS1. Furthermore, influenza virus down-regulates Nup98, a nucleoporin that is a docking site for mRNA export factors. Reduced expression of these mRNA export factors renders cells highly permissive to influenza virus replication, demonstrating that proper levels of key constituents of the mRNA export machinery protect against influenza virus replication. Because Nup98 and Rae1 are induced by interferons, downregulation of this pathway is likely a viral strategy to promote viral replication. These findings demonstrate previously undescribed influenza-mediated viral-host interactions and provide insights into potential molecular therapies that may interfere with influenza infection.NS1 ͉ nucleoporin ͉ nuclear transport ͉ mRNA nuclear export

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Regulation of Hepatitis C Virus Replication by Interferon Regulatory Factor 1

Cited by 83 publications

References 49 publications

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

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

Interferon regulatory factor‐1 is prerequisite to the constitutive expression and IFN‐γ‐induced upregulation of B7‐H1 (CD274)

Influenza virus targets the mRNA export machinery and the nuclear pore complex

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