1887

Abstract

Identification of host factors involved in viral replication is critical for understanding the molecular mechanism of viral replication and pathogenesis. Genes differentially expressed in HuH-7 cells with or without a hepatitis C virus (HCV) sub-genomic replicon were screened by microarray analysis. SERPINE1/PAI-1 was found to be down-regulated after HCV infection in this analysis. Down-regulation of SERPINE1/PAI-1 expression at the transcriptional level was verified by the real-time reverse transcriptase (RT)-PCR assay. Reduced SERPINE1/PAI-1 protein secretion was detected in the supernatant of HCV replicon cells and in sera from HCV-infected patients. SERPINE1 gene expression was down-regulated by HCV NS3/4A and NS5A proteins through the transforming growth factor-β (TGF-β) signalling pathway at the transcriptional level. Down-regulated genes in HCV replicon cells could be the factors supressing HCV replication. Indeed, over-expressed PAI-1 inhibited HCV replication but the mechanism is unknown. It has been demonstrated that HCV induces the expression of TGF-β, and TGF-β enhances HCV replication by a not-yet-defined mechanism. SERPINE1/PAI-1 is also known to be potently induced by TGF-β at the transcriptional level through both Smad-dependent and Smad–independent pathways. The exogenously expressed SERPINE1/PAI-1 suppressed the expression of the endogenous SERPINE1 gene at the transcriptional level through the TGF-β signalling but not the Smad pathway. Thus, SERPINE1/PAI-1 could suppress HCV replication possibly by negatively regulating TGF-β signalling. A model is proposed for the interplay betweenthe TGF-β signalling pathway, HCV and SERPINE1/PAI-1 to keep the homeostasis of the cells.

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2017-08-31
2019-09-16
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References

  1. Scheel TK, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med 2013;19:837–849 [CrossRef][PubMed]
    [Google Scholar]
  2. Moustakas A, Heldin CH. Non-Smad TGF-β signals. J Cell Sci 2005;118:3573–3584 [CrossRef][PubMed]
    [Google Scholar]
  3. Li HC, Lo SY. Hepatitis C virus: virology, diagnosis and treatment. World J Hepatol 2015;7:1377–1389 [CrossRef][PubMed]
    [Google Scholar]
  4. Au JS, Pockros PJ. Novel therapeutic approaches for hepatitis C. Clin Pharmacol Ther 2014;95:78–88 [CrossRef][PubMed]
    [Google Scholar]
  5. Manns MP, von Hahn T. Novel therapies for hepatitis C – one pill fits all?. Nat Rev Drug Discov 2013;12:595–610 [CrossRef][PubMed]
    [Google Scholar]
  6. Rice CM, Saeed M. Hepatitis C: treatment triumphs. Nature 2014;510:43–44 [CrossRef][PubMed]
    [Google Scholar]
  7. Randall G, Panis M, Cooper JD, Tellinghuisen TL, Sukhodolets KE et al. Cellular cofactors affecting hepatitis C virus infection and replication. Proc Natl Acad Sci USA 2007;104:12884–12889 [CrossRef][PubMed]
    [Google Scholar]
  8. Ploss A, Evans MJ, Gaysinskaya VA, Panis M, You H et al. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 2009;457:882–886 [CrossRef][PubMed]
    [Google Scholar]
  9. Zhang Y, Alexander PB, Wang XF. TGF-β Family signaling in the control of cell proliferation and survival. Cold Spring Harb Perspect Biol 2017;9:a022145 [CrossRef][PubMed]
    [Google Scholar]
  10. Chusri P, Kumthip K, Hong J, Zhu C, Duan X et al. HCV induces transforming growth factor β1 through activation of endoplasmic reticulum stress and the unfolded protein response. Sci Rep 2016;6:22487 [CrossRef][PubMed]
    [Google Scholar]
  11. Ray S, Broor SL, Vaishnav Y, Sarkar C, Girish R et al. Transforming growth factor beta in hepatitis C virus infection: in vivo and in vitro findings. J Gastroenterol Hepatol 2003;18:393–403 [CrossRef][PubMed]
    [Google Scholar]
  12. Goto K, Lin W, Zhang L, Jilg N, Shao RX et al. The AMPK-related kinase SNARK regulates hepatitis C virus replication and pathogenesis through enhancement of TGF-β signaling. J Hepatol 2013;59:942–948 [CrossRef][PubMed]
    [Google Scholar]
  13. Taylor AW. Review of the activation of TGF-β in immunity. J Leukoc Biol 2009;85:29–33 [CrossRef][PubMed]
    [Google Scholar]
  14. Samarakoon R, Overstreet JM, Higgins SP, Higgins PJ. TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis. Cell Tissue Res 2012;347:117–128 [CrossRef][PubMed]
    [Google Scholar]
  15. Ten Dijke P, Hill CS. New insights into TGF-β-Smad signalling. Trends Biochem Sci 2004;29:265–273 [CrossRef][PubMed]
    [Google Scholar]
  16. Samarakoon R, Higgins PJ. Integration of non-SMAD and SMAD signaling in TGF-β1-induced plasminogen activator inhibitor type-1 gene expression in vascular smooth muscle cells. Thromb Haemost 2008;100:976–983[PubMed]
    [Google Scholar]
  17. Dennler S, Itoh S, Vivien D, Ten Dijke P, Huet S et al. Direct binding of Smad3 and Smad4 to critical TGF β-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. Embo J 1998;17:3091–3100 [CrossRef][PubMed]
    [Google Scholar]
  18. Vayalil PK, Iles KE, Choi J, Yi AK, Postlethwait EM et al. Glutathione suppresses TGF-β-induced PAI-1 expression by inhibiting p38 and JNK MAPK and the binding of AP-1, SP-1, and Smad to the PAI-1 promoter. Am J Physiol Lung Cell Mol Physiol 2007;293:L1281–L1292 [CrossRef][PubMed]
    [Google Scholar]
  19. Choi SH, Hwang SB. Modulation of the transforming growth factor-β signal transduction pathway by hepatitis C virus nonstructural 5A protein. J Biol Chem 2006;281:7468–7478 [CrossRef][PubMed]
    [Google Scholar]
  20. Cheng PL, Chang MH, Chao CH, Lee YH. Hepatitis C viral proteins interact with Smad3 and differentially regulate TGF-β/Smad3-mediated transcriptional activation. Oncogene 2004;23:7821–7838 [CrossRef][PubMed]
    [Google Scholar]
  21. Czekay RP, Wilkins-Port CE, Higgins SP, Freytag J, Overstreet JM et al. PAI-1: an integrator of cell signaling and migration. Int J Cell Biol 2011;2011:1–9 [CrossRef][PubMed]
    [Google Scholar]
  22. Declerck PJ, Gils A. Three decades of research on plasminogen activator inhibitor-1: a multifaceted serpin. Semin Thromb Hemost 2013;39:356–364 [CrossRef][PubMed]
    [Google Scholar]
  23. Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 2001;108:779–784 [CrossRef][PubMed]
    [Google Scholar]
  24. Olson D, Pöllänen J, Høyer-Hansen G, Rønne E, Sakaguchi K et al. Internalization of the urokinase-plasminogen activator inhibitor type-1 complex is mediated by the urokinase receptor. J Biol Chem 1992;267:9129–9133[PubMed]
    [Google Scholar]
  25. Grakoui A, McCourt DW, Wychowski C, Feinstone SM, Rice CM. Characterization of the hepatitis C virus-encoded serine proteinase: determination of proteinase-dependent polyprotein cleavage sites. J Virol 1993;67:2832–2843[PubMed]
    [Google Scholar]
  26. Lawrence DA, Olson ST, Palaniappan S, Ginsburg D. Serpin reactive center loop mobility is required for inhibitor function but not for enzyme recognition. J Biol Chem 1994;269:27657–27662[PubMed]
    [Google Scholar]
  27. Nakashima K, Takeuchi K, Chihara K, Hotta H, Sada K. Inhibition of hepatitis C virus replication through adenosine monophosphate-activated protein kinase-dependent and -independent pathways. Microbiol Immunol 2011;55:774–782 [CrossRef][PubMed]
    [Google Scholar]
  28. Mishra R, Cool BL, Laderoute KR, Foretz M, Viollet B et al. AMP-activated protein kinase inhibits transforming growth factor-β-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J Biol Chem 2008;283:10461–10469 [CrossRef][PubMed]
    [Google Scholar]
  29. Samarakoon R, Higgins SP, Higgins CE, Higgins PJ. TGF-β1-induced plasminogen activator inhibitor-1 expression in vascular smooth muscle cells requires pp60c-src/EGFRY845 and Rho/ROCK signaling. J Mol Cell Cardiol 2008;44:527–538 [CrossRef][PubMed]
    [Google Scholar]
  30. Pan RY, Hung TM, Kou YH, Chan NL, Chang MF et al. In trans interaction of hepatitis C virus helicase domains mediates protease activity critical for internal NS3 cleavage and cell transformation. FEBS Lett 2010;584:482–486 [CrossRef][PubMed]
    [Google Scholar]
  31. Law RH, Zhang Q, Mcgowan S, Buckle AM, Silverman GA et al. An overview of the serpin superfamily. Genome Biol 2006;7:216 [CrossRef][PubMed]
    [Google Scholar]
  32. Dittmann M, Hoffmann HH, Scull MA, Gilmore RH, Bell KL et al. A serpin shapes the extracellular environment to prevent influenza A virus maturation. Cell 2015;160:631–643 [CrossRef][PubMed]
    [Google Scholar]
  33. Asmal M, Seaman M, Lin W, Chung RT, Letvin NL et al. Inhibition of HCV by the serpin antithrombin III. Virol J 2012;9:226 [CrossRef][PubMed]
    [Google Scholar]
  34. Sureshbabu A, Muhsin SA, Choi ME. TGF-β signaling in the kidney: profibrotic and protective effects. Am J Physiol Renal Physiol 2016;310:F596–F606 [CrossRef][PubMed]
    [Google Scholar]
  35. Vaughan DE. PAI-1 and TGF-β: unmasking the real driver of TGF-β-induced vascular pathology. Arterioscler Thromb Vasc Biol 2006;26:679–680 [CrossRef][PubMed]
    [Google Scholar]
  36. Fang CP, Li ZC, Yang CH, Cheng JC, Yeh YJ et al. Hepatitis C virus non-structural protein 3 interacts with cytosolic 5'(3')-deoxyribonucleotidase and partially inhibits its activity. PLoS One 2013;8:e68736 [CrossRef][PubMed]
    [Google Scholar]
  37. Ma HC, Fang CP, Hsieh YC, Chen SC, Li HC et al. Expression and membrane integration of SARS-CoV M protein. J Biomed Sci 2008;15:301–310 [CrossRef][PubMed]
    [Google Scholar]
  38. Chang CW, Li HC, Hsu CF, Chang CY, Lo SY. Increased ATP generation in the host cell is required for efficient vaccinia virus production. J Biomed Sci 2009;16:80 [CrossRef][PubMed]
    [Google Scholar]
  39. Hu WT, Li HC, Lee SK, Ma HC, Yang CH et al. Both core and F proteins of hepatitis C virus could enhance cell proliferation in transgenic mice. Biochem Biophys Res Commun 2013;435:147–152 [CrossRef][PubMed]
    [Google Scholar]
  40. Chen JS, Li HC, Lin SI, Yang CH, Chien WY et al. Cleavage of Dicer protein by I7 protease during vaccinia virus infection. PLoS One 2015;10:e0120390 [CrossRef][PubMed]
    [Google Scholar]
  41. Ma HC, Lin TW, Li H, Iguchi-Ariga SM, Ariga H et al. Hepatitis C virus ARFP/F protein interacts with cellular MM-1 protein and enhances the gene trans-activation activity of c-Myc. J Biomed Sci 2008;15:417–425 [CrossRef][PubMed]
    [Google Scholar]
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