Hepatitis C virus NS5A protein protects against TNF-α mediated apoptotic cell death

Ghosh, Asish K.; Majumder, Mainak; Steele, Robert; Meyer, Keith; Ray, R.K.; Ray, Ratna B.

doi:10.1016/s0168-1702(00)00141-6

Cited by 84 publications

(56 citation statements)

References 22 publications

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“…Although the development of HCC is certainly influenced by a combination of viral, host, and environmental factors, the data presented here suggest that NS5A-mediated stabilization of ␤-catenin may be a contributing factor in the association between HCV infection and HCC. This hypothesis is strengthened by previous results from our laboratory (45) and others (7,21,36) showing that NS5A mediates an increase in the resistance of cells to proapoptotic stimuli by a variety of mechanisms. As well as direct effects on the PI3K pathway, NS5A has been reported to bind to and inhibit both p53 (29) and Bax (7), thereby blocking the apoptotic response.…”

Section: Discussionsupporting

confidence: 54%

Hepatitis C Virus NS5A-Mediated Activation of Phosphoinositide 3-Kinase Results in Stabilization of Cellular β-Catenin and Stimulation of β-Catenin-Responsive Transcription

Street

Macdonald

McCormick

et al. 2005

J Virol

133

114

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The hepatitis C virus (HCV) nonstructural NS5A protein has been shown to bind to and activate phosphoinositide 3-kinase (PI3K), resulting in activation of the downstream effector serine/threonine kinase Akt/ protein kinase B. Here we present data pertaining to the effects of NS5A-mediated Akt activation on its downstream targets. Using a recombinant baculovirus to deliver the complete HCV polyprotein to human hepatoma cells in a tetracycline-regulable fashion, we confirm that expression of the complete HCV polyprotein also activates PI3K and Akt. We further show that this results in the inhibition of the Akt substrate Forkhead transcription factor and the stimulation of phosphorylation of a second key Akt substrate, glycogen synthase kinase-3␤ (GSK-3␤). Phosphorylation of GSK-3␤ results in its inactivation; consistent with this, we show that expression of the HCV polyprotein results in the accumulation of ␤-catenin. Finally, we show that levels of ␤-catenin-dependent transcription are also elevated in the presence of the HCV polyprotein. Given the prevalence of ␤-catenin mutations in many human tumors, especially colon and hepatocellular carcinomas, these data implicate NS5A-mediated PI3K activation as a contributory factor in the increasingly common association between HCV infection and the development of hepatocellular carcinoma.Hepatitis C virus (HCV) is recognized as a major public health problem; the World Health Organization estimates that as many as 170 million individuals (approximately 3% of the world population) are infected with this virus. In 85% of cases, the virus establishes a chronic infection, culminating in chronic inflammation, cirrhosis, and, increasingly, hepatocellular carcinoma (HCC). Indeed, HCV is now the leading cause of HCC and is the most common reason for liver transplantation in the West (47). Treatment is presently limited to the use of type 1 interferon in combination with the nucleoside analogue ribavirin; this therapeutic regime is successful in 40 to 80% of patients, depending on virus genotype.The HCV genome is a single-stranded positive-sense 9.6-kb RNA molecule, comprising a single open reading frame coding for a polyprotein of ϳ3,000 amino acids flanked by untranslated regions (UTRs). The 5Ј UTR contains an internal ribosome entry sequence, allowing cap-independent initiation of translation. The polyprotein is cleaved into 10 polypeptides by cellular and viral proteinases; one of these products is the nonstructural NS5A protein. NS5A has been the focus of much intensive investigation recently with regard to its potential role both in the cytopathology of HCV infection and in mediating viral immune evasion (for a review, see reference 33). NS5A has been reported to interact with a wide range of cellular proteins involved in, among others, the interferon response and cell cycle control. These interactions result in the modulation of various transcription factors, including NF-B (40, 46), STAT3 (31, 43), and AP-1 (32); furthermore, NS5A has been reported to promote anchorage-i...

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Section: Discussionsupporting

confidence: 54%

Hepatitis C Virus NS5A-Mediated Activation of Phosphoinositide 3-Kinase Results in Stabilization of Cellular β-Catenin and Stimulation of β-Catenin-Responsive Transcription

Street

Macdonald

McCormick

et al. 2005

J Virol

133

114

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“…NS5A provides resistance to apoptosis induced by PKR agonists, such as dsRNA, and can cause cell transformation and solid-tumor growth in vivo through both PKR-dependent and -independent mechanisms (19). In addition, NS5A has also been reported to modulate cell cycle regulatory genes and protect against tumor necrosis factor alpha-mediated apoptotic cell death (22,23). However, the exact molecular mechanisms by which NS5A regulates cell survival and apoptosis await further characterization.…”

mentioning

confidence: 99%

“…6F), demonstrating the ability of NS5A to modulate the apoptosis machinery through the PI3K-AKT pathway during both cellular signaling and viral infection. Upregulation of the PI3K-AKT-BAD pathway may contribute to the antiapoptotic and oncogenic abilities of NS5A (19,22).…”

mentioning

confidence: 99%

Subversion of Cell Signaling Pathways by Hepatitis C Virus Nonstructural 5A Protein via Interaction with Grb2 and P85 Phosphatidylinositol 3-Kinase

Nakao²,

Tan³

et al. 2002

J Virol

162

128

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Hepatitis C virus (HCV) sets up a persistent infection in patients that likely involves a complex virus-host interaction. We previously found that the HCV nonstructural 5A (NS5A) protein interacts with growth factor receptor-binding protein 2 (Grb2) adaptor protein and inhibits the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by epidermal growth factor (EGF). In the present study, we extended this analysis and investigated the specificity of the Grb2-NS5A interaction and whether the subversion of mitogenic signaling involves additional pathways. NS5A containing mutations within the C-terminal proline-rich motif neither bound Grb2 nor inhibited ERK1/2 activation by EGF, demonstrating that NS5A-Grb2 binding and downstream effects were due to direct interactions. Interestingly, NS5A could also form a complex with the Grb2-associated binder 1 (Gab1) protein in an EGF treatment-dependent manner. However, the NS5A-Gab1 association, which appeared indirect, was not mediated by direct NS5A-Grb2 interaction but was likely dependent on direct NS5A interaction with the p85 subunit of phosphatidylinositol 3-kinase (PI3K). The in vivo association of NS5A with p85 PI3K required the N-terminal, but not the C-terminal, region of NS5A. The downstream effects of the NS5A-p85 PI3K interaction included increased tyrosine phosphorylation of p85 PI3K in response to EGF. Consistent with this observation and the antiapoptotic properties of NS5A, we also detected enhanced tyrosine phosphorylation of the downstream AKT protein kinase and increased serine phosphorylation of BAD, a proapoptotic factor and an AKT substrate, in the presence of NS5A. These results collectively suggest a model in which NS5A interacts with Grb2 to inhibit mitogenic signaling while simultaneously promoting the PI3K-AKT cell survival pathway by interaction with p85 PI3K, which may represent a crucial step in HCV persistence and pathogenesis.Hepatitis C virus (HCV), a Flaviviridae family member, contains a positive-sense, single-stranded RNA genome that encodes about 10 mature viral structural and nonstructural (NS) proteins (41). Infecting approximately 2% of the world population, HCV is the global leading cause of chronic liver disease and has become a major public health problem in the United States (10, 11). In the majority of cases, acute infection with HCV results in persistent viral replication and establishment of a chronic infection. Chronic hepatitis C frequently leads to progressive liver disease, including liver fibrosis and cirrhosis, and is strongly associated with the onset of hepatocellular carcinoma. HCV research has been hampered by the lack of an efficient tissue culture system or an adequate animal model of HCV infection (18). As a result, the mechanisms of HCV replication, persistence, and pathogenesis remain poorly understood. Consequently, our general understanding of the impact of HCV infection on cellular signaling is far from complete or clear.HCV-host interactions have been intensely investigated despite the lack...

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“…Mapping studies found that ISDR and the adjacent C-terminal 26 amino acids can form a heterodimer with PKR. The effect of HCV NS5A on the protection of apoptosis induced by TNF-α and p53 was further identified [16,17] . In the present study, we explored the possible effect of HCV NS5A on the transactivation of p53.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies showed that HCV NS5A could interact with a number of cellular proteins including PKR, p53, Grb2 and Cdk1 [7][8][9][10] , and enhance expression of some genes related to cell proliferation such as PCNA, NF-κB, Stat-3, SRCAP and IL-8 [11][12][13][14] , indicating that HCV NS5A has a critical role in promoting cell proliferation and malignant transformation. HCV NS5A prevents p53 and TNF-a mediated apoptosis [15][16][17] , and possibly perturbs the DNA repair when cells are treated with DNA damage agents including viruses, toxins or physical damage. HCV NS5A is important for the HCV replication.…”

Section: Introductionmentioning

confidence: 99%

HCV NS5A abrogates p53 protein function by interfering with p53-DNA binding

Gong

Jiang²,

He³

et al. 2004

WJG

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Hepatitis C virus NS5A protein protects against TNF-α mediated apoptotic cell death

Cited by 84 publications

References 22 publications

Hepatitis C Virus NS5A-Mediated Activation of Phosphoinositide 3-Kinase Results in Stabilization of Cellular β-Catenin and Stimulation of β-Catenin-Responsive Transcription

Hepatitis C Virus NS5A-Mediated Activation of Phosphoinositide 3-Kinase Results in Stabilization of Cellular β-Catenin and Stimulation of β-Catenin-Responsive Transcription

Subversion of Cell Signaling Pathways by Hepatitis C Virus Nonstructural 5A Protein via Interaction with Grb2 and P85 Phosphatidylinositol 3-Kinase

HCV NS5A abrogates p53 protein function by interfering with p53-DNA binding

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