Molecular Determinants of TRIF Proteolysis Mediated by the Hepatitis C Virus NS3/4A Protease

Ferreon, Josephine C.; Ferreon, Allan Chris M.; Li, Kui; Lemon, Stanley M.

doi:10.1074/jbc.m500422200

Cited by 116 publications

(83 citation statements)

References 57 publications

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“…It is interesting to note that the TRIF cleavage site (PSSTPC↓SAHLT) differs from the HCV consensus cleavage site by a proline at the P6 position instead of an acidic residue. Strikingly, this proline is preceded by a stretch of 7 prolines and it is thought that this particular sequence may enhance the affinity of TRIF for the NS3 protease [73] . This stretch of proline, which can form a left-handed polyproline II helix may compensate for the absence of acidic residue at the P6 position, which normally is contributing to enhance the Km values in the viral natural substrates.…”

Section: Ifn Inducing Pathwaysmentioning

confidence: 99%

The interferon inducing pathways and the hepatitis C virus

Meurs

Breiman

2007

WJG

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The innate immune response is triggered by a variety of pathogens, including viruses, and requires rapid induction of type I interferons (IFN), such as IFNβ and IFNα. IFN induction occurs when specific pathogen motifs bind to specific cellular receptors. In non-professional immune, virally-infected cells, IFN induction is essentially initiated after the binding of dsRNA structures to TLR3 receptors or to intracytosolic RNA helicases, such as RIG-I /MDA5. This leads to the recruitment of specific adaptors, such as TRIF for TLR3 and the mitochondrial-associated IPS-1/VISA/MAVS/CARDIF adapter protein for the RNA helicases, and the ultimate recruitment of kinases, such as MAPKs, the canonical IKK complex and the TBK1/IKKε kinases, which activate the transcription factors ATF-2/ c-jun, NF-κB and IRF3, respectively. The coordinated action of these transcription factors leads to induction of IFN and of pro-inflammatory cytokines and to the establishment of the innate immune response. HCV can cleave both the adapters TRIF and IPS-1/VISA/MAVS/ CARDIF through the action of its NS3/4A protease. This provokes abrogation of the induction of the IFN and cytokine pathways and favours viral propagation and presumably HCV chronic infection.

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Section: Ifn Inducing Pathwaysmentioning

confidence: 99%

The interferon inducing pathways and the hepatitis C virus

Meurs

Breiman

2007

WJG

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“…Eventually, the IKK-related kinases IKKe and Tank-binding kinase 1 (TBK1) are activated and they in turn activate nuclear factor (NF)-kB and IFN regulatory factor 3 (IRF3) transcription factors, which translocate into the nucleus and initiate the transcription of type I IFN genes (Wathelet et al, 1998). The NS3/4A protein complex may target both TRIF (Ferreon et al, 2005;Li et al, 2005a) and Cardif (Kaukinen et al, 2006;Li et al, 2005b;Lin et al, 2006a;Loo et al, 2006;Meylan et al, 2005), causing their proteolytic degradation. In addition, there is evidence that NS3 can interact directly with TBK1 and IKKe (Otsuka et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus proteins interfere with the activation of chemokine gene promoters and downregulate chemokine gene expression

Sillanpää

Kaukinen

Melén

et al. 2008

Journal of General Virology

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The hepatitis C virus (HCV) non-structural (NS) 3/4A protein complex inhibits the retinoic acid inducible gene I (RIG-I) pathway by proteolytically cleaving mitochondria-associated CARD-containing adaptor protein Cardif, and this leads to reduced production of beta interferon (IFN-b). This study examined the expression of CCL5 (regulated upon activation, normal T-cell expressed and secreted, or RANTES), CXCL8 (interleukin 8) and CXCL10 (IFN-c-activated protein 10, or IP-10) chemokine genes in osteosarcoma cell lines that inducibly expressed NS3/4A, NS4B, core-E1-E2-p7 and the entire HCV polyprotein. Sendai virus (SeV)-induced production of IFN-b, CCL5, CXCL8 and CXCL10 was downregulated by the NS3/4A protein complex and by the full-length HCV polyprotein. Expression of NS3/4A and the HCV polyprotein reduced the binding of interferon regulatory factors (IRFs) 1 and 3 and, to a lesser extent, nuclear factor (NF)-kB (p65/p50) to their respective binding elements on the CXCL10 promoter during SeV infection. Furthermore, binding of IRF1 and IRF3 to the interferon-stimulated response element-like element, and of c-Jun and phosphorylated c-Jun to the activator protein 1 element of the CXCL8 promoter, was reduced when NS3/4A and the HCV polyprotein were expressed. In cell lines expressing NS3/4A and the HCV polyprotein, the subcellular localization of mitochondria was changed, and this was kinetically associated with the partial degradation of endogenous Cardif. These results indicate that NS3/4A alone or as part of the HCV polyprotein disturbs the expression of IRF1-and IRF3-regulated genes, as well as affecting mitogen-activated protein kinase kinase-and NF-kB-regulated genes. INTRODUCTIONHepatitis C virus (HCV) belongs to the family Flaviviridae. Its single-stranded RNA genome is 9.6 kb and encodes a large polyprotein that is cleaved into 11 structural and non-structural (NS) proteins by cellular and viral-encoded proteases. The structural region of the HCV genome contains the core, E1, E2 and p7 proteins and an alternative reading frame protein (Moradpour et al., 2002). The core protein forms the viral nucleocapsid, E1 and E2 are viral envelope glycoproteins, and p7 functions as a cation channel (Griffin et al., 2003). The HCV genome also encodes six NS proteins. NS2 is a cysteine protease and NS3 a serine protease, and they are involved in processing of the HCV polyprotein. NS3 also functions as an RNA helicase. NS4A is an essential co-factor for NS3 protease activity. NS4B is a membrane-associated protein with no assigned functions, NS5A is a phosphoprotein and NS5B is an RNA-dependent RNA polymerase (Lindenbach & Rice, 2005;Moradpour et al., 2002).In the early stages of virus infection, the production of the antiviral cytokines alpha and beta interferon (IFN-a/b) and several proinflammatory chemokines such as CCL5 [regulated upon activation, normal T-cell expressed and secreted (RANTES)], CXCL8 [interleukin (IL) 8], and CXCL10 [IFNc-activated protein 10 (IP-10)] are activated. These chemokines are chemoattractive...

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“…The structural protein E2 (72) and the nonstructural protein NS5A (22,23) modulate interferon responses by inhibiting the interferoninducible double-stranded RNA-dependent protein kinase R (PKR). The NS3/4A protease functions as an antagonist of virus-induced interferon regulatory factor 3 (IRF-3) and NF-B activation and IFN-␤ expression by blocking the Tolllike receptor 3 and retinoic acid-inducible gene I signaling pathways (17,18,37). This signaling block not only impairs IFN production in hepatocytes but also breaks the IFN amplification loop (8,18), thereby inhibiting the expression of several ISGs, including those involved in the adaptive immune response (for a review, see reference 21).…”

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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Molecular Determinants of TRIF Proteolysis Mediated by the Hepatitis C Virus NS3/4A Protease

Cited by 116 publications

References 57 publications

The interferon inducing pathways and the hepatitis C virus

The interferon inducing pathways and the hepatitis C virus

Hepatitis C virus proteins interfere with the activation of chemokine gene promoters and downregulate chemokine gene expression

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

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