NS5ATP9, a gene up-regulated by HCV NS5A protein

Shi, Lei; Zhang, Shulin; Li, Kang; Yuan, Hong; Wang, Qi; Li, Yue; Guo, Jiang; Fan, Wanhu; Zhang, Lei; Cheng, Jun

doi:10.1016/j.canlet.2007.10.029

Cited by 19 publications

(26 citation statements)

References 20 publications

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“…Among its numerous properties, the HCV NS5A protein has been shown to bear transcriptional activation properties in yeast (Saccharomyces cerevisiae) and mammalian cells (10)(11)(12)(13). These properties are borne by a transcriptional activation domain, comprised of two acidic regions followed by a proline-rich region spanning amino acids 2135 to 2331 of the protein (reference strain HCV-J) (11).…”

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confidence: 99%

Regulation of Hepatitis C Virus Replication by Nuclear Translocation of Nonstructural 5A Protein and Transcriptional Activation of Host Genes

Maqbool

Imache

Higgs

et al. 2013

J Virol

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bHepatitis C virus (HCV) nonstructural protein 5A (NS5A) is involved in regulating viral replication through its direct interaction with the HCV RNA-dependent RNA polymerase. NS5A also alters infected cell metabolism through complex interactions with numerous host cell proteins. NS5A has furthermore been suggested to act as a transcriptional activator, although the impact on viral replication is unclear. To study this, HCV NS5A variants were amplified from hepatic tissue from an HCV-infected patient, and their abilities to activate gene transcription were analyzed in a single-hybrid yeast (Saccharomyces cerevisiae) model. Different variants isolated from the same patient displayed different transactivational activities. When these variants were inserted into the HCV subgenomic replicon system, they demonstrated various levels of RNA replication, which correlated with their transactivational activities. We showed that the C-terminal fragment of NS5A was localized to the nucleus and that a functional NS5A nuclear localization signal and cellular caspase activity were required for this process. Furthermore, nuclear localization of NS5A was necessary for viral replication. Finally, we demonstrate that nuclear NS5A binds to host cell promoters of several genes previously identified as important for efficient HCV RNA replication, inducing their transcription. Taken together, these results demonstrate a new mechanism by which HCV modulates its cellular environment, thereby enhancing viral replication. H epatitis C virus (HCV) infection is characterized by a highfrequency of chronicity and is responsible for chronic infection of approximately 130 million carriers-i.e., 2.2% of the worldwide population (1). Chronic HCV infection is responsible for chronic hepatitis, a major risk factor in the development of cirrhosis and hepatocellular carcinoma (HCC) or primary liver cancer, which occurs in 1 to 4% of cirrhotic patients every year (2, 3). Chronic HCV infection has become the principal cause of HCC in Japan, and modeling of the ongoing epidemics predicts a similar trend in Europe (4, 5).HCV is an enveloped, positive-strand RNA virus with a cytoplasmic life cycle. HCV replication is catalyzed by an RNA-dependent RNA polymerase (RdRp). It takes place within a membranous web (replication complex) located close to perinuclear membranes, in close association with the nonstructural HCV proteins and a number of host cell factors that play an important role in this process (6, 7). The precise functions of HCV nonstructural protein 5A (NS5A) remains largely unclear. However, it has been shown to be a pleiotropic serine phosphoprotein, involved in the regulation of RdRp function as well as in a number of interactions with host cell mechanisms (8). Studies have also suggested a role for NS5A in the establishment of chronicity of HCV infection and in procarcinogenic events (9).Among its numerous properties, the HCV NS5A protein has been shown to bear transcriptional activation properties in yeast (Saccharomyces cerevisiae) and mamma...

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confidence: 99%

Regulation of Hepatitis C Virus Replication by Nuclear Translocation of Nonstructural 5A Protein and Transcriptional Activation of Host Genes

Maqbool

Imache

Higgs

et al. 2013

J Virol

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“…To ensure that, patients were screened for the absence of HBV, HCV and schistosomal infections and the involvement of HCV infection was confirmed with RT-PCR. The mechanism through which HCV leads to hepatic dysfunction was repeatedly reported, where the viral proteins usually transactivate many of the host cell genes [18]. Thus HCVinduced transformation of infected cells reflects the phenotypical changes (seen in chronically infected liver), which progressed gradually over years.…”

Section: Discussionmentioning

confidence: 99%

Monitoring Coagulation Proteins During Progression of Liver Disease

et al. 2014

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This work was designated to monitor the coagulation abnormalities associated with the gradual progression of liver diseases. The study included fifty patients; forty were diagnosed with liver cirrhosis with different stages categorized according to the Childs-Pugh classification and another ten patients were diagnosed with hepatocellular carcinoma (HCC). Haemostatic variables including fibrinogen (FI), calcium (FIV), transglutaminase (FXIII), prothrombin time (PT) and platelet count were estimated in patients and compared with the baseline levels of healthy subjects (n = 10). The results demonstrated that the fibrinogen level was progressively decreased, whereas PT was progressively prolonged in Child A, Child B and Child C groups. The maximum deterioration was observed in HCC patients. Calcium significantly increased in mild (Child A) and moderate (Child B) but not in Child C cirrhosis and HCC patients. FXIII level did not show any significant changes in cirrhotic patients compared to healthy group. Some of the haemostatic variables we investigated were correlated with serum albumin and bilirubin but not with aminotransferases (ALT and AST). The results indicated that the haemostatic abnormalities in fibrinogen, calcium and PT (but not FXIII) were deteriorated in parallel with the gradual regression of the constitutional function of liver.

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“…Our previous study found that NS5ATP9 might play a role in the pathogenesis of HCV-associated HCC [8]. However, few studies reported on the correlation between NS5ATP9 and HSC activation.…”

Section: Discussionmentioning

confidence: 99%

“…The gene product of NS5ATP9 was originally identified as a proliferating cell nuclear antigen-binding protein by a yeast two-hybrid assay [7] and as a target gene Mengran Zhang and Jinqian Zhang contributed equally to this work Electronic supplementary material The online version of this article (doi:10.1007/s10753-014-0031-y) contains supplementary material, which is available to authorized users. transactivated by the hepatitis C virus (HCV) NS5A protein via the suppression subtractive hybridization technique by our group [8]. NS5ATP9 expression was significantly altered in numerous malignant tumors, including pancreatic cancer, colorectal adenoma and adenocarcinoma, nonsmall cell lung cancer, anaplastic thyroid carcinoma, and liver cancer [9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

NS5ATP9 Suppresses Activation of Human Hepatic Stellate Cells, Possibly via Inhibition of Smad3/Phosphorylated-Smad3 Expression

Zhang

Liu

et al. 2014

Inflammation

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Activation of hepatic stellate cell (HSC) is the central event in liver fibrosis. NS5ATP9 is related to many malignant tumors, but little is known about its function in HSC activation. The aim of this study is to investigate the role of NS5ATP9 in HSC activation in vitro. Genes related to liver fibrosis were detected after NS5ATP9 overexpression or silencing with or without transforming growth factor (TGF)-β1 stimulation in the human HSCs by real-time polymerase chain reaction and western blotting. Cell proliferation, migration, and apoptosis were tested, and the mechanisms underlying the effect of NS5ATP9 on HSC activation were studied. We showed that NS5ATP9 suppressed HSC activation and collagen production, with or without TGF-β1 induction. Also, NS5ATP9 inhibited cell proliferation and migration and promoted apoptosis. Furthermore, NS5ATP9 reduced basal and TGF-β1-mediated Smad3/phosphorylated-Smad3 expression. The existence of a physical complex between NS5ATP9 and Smad3 was illustrated. NS5ATP9 suppresses HSC activation, extracellular matrix production, and promotes apoptosis, in part through reducing Smad3/phosphorylated-Smad3 expression.

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NS5ATP9, a gene up-regulated by HCV NS5A protein

Cited by 19 publications

References 20 publications

Regulation of Hepatitis C Virus Replication by Nuclear Translocation of Nonstructural 5A Protein and Transcriptional Activation of Host Genes

Regulation of Hepatitis C Virus Replication by Nuclear Translocation of Nonstructural 5A Protein and Transcriptional Activation of Host Genes

Monitoring Coagulation Proteins During Progression of Liver Disease

NS5ATP9 Suppresses Activation of Human Hepatic Stellate Cells, Possibly via Inhibition of Smad3/Phosphorylated-Smad3 Expression

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