1887

Journal of General Virology header logo

Volume 98, Issue 9

Hepatitis C virus down-regulates SERPINE1/PAI-1 expression to facilitate its replication Free

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. 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 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.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): hepatitis C virus , NS3 , NS5A , SERPINE1/PAI-1 and TGF-β
© 2017 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000901
2017-09-01
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/jgv/98/9/2274.html?itemId=/content/journal/jgv/10.1099/jgv.0.000901&mimeType=html&fmt=ahah

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 [View Article][PubMed]
     [Google Scholar]
  2. Moustakas A, Heldin CH. Non-Smad TGF-β signals. J Cell Sci 2005; 118:3573–3584 [View Article][PubMed]
     [Google Scholar]
  3. Li HC, Lo SY. Hepatitis C virus: virology, diagnosis and treatment. World J Hepatol 2015; 7:1377–1389 [View Article][PubMed]
     [Google Scholar]
  4. Au JS, Pockros PJ. Novel therapeutic approaches for hepatitis C. Clin Pharmacol Ther 2014; 95:78–88 [View Article][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 [View Article][PubMed]
     [Google Scholar]
  6. Rice CM, Saeed M. Hepatitis C: treatment triumphs. Nature 2014; 510:43–44 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][PubMed]
     [Google Scholar]
  13. Taylor AW. Review of the activation of TGF-β in immunity. J Leukoc Biol 2009; 85:29–33 [View Article][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 [View Article][PubMed]
     [Google Scholar]
  15. Ten Dijke P, Hill CS. New insights into TGF-β-Smad signalling. Trends Biochem Sci 2004; 29:265–273 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][PubMed]
     [Google Scholar]
  23. Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest 2001; 108:779–784 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][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 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000901
Loading
Hepatitis C virus down-regulates SERPINE1/PAI-1 expression to facilitate its replication
J. Gen. Virol. 98, 2274 (2017); https://doi.org/10.1099/jgv.0.000901
/content/journal/jgv/10.1099/jgv.0.000901
/content/journal/jgv/10.1099/jgv.0.000901
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error