1887

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Volume 97, Issue 12

Inhibition of hepatitis B virus replication by activation of the cGAS-STING pathway Free

Abstract

Cyclic GMP-AMP (cGAMP) synthase (cGAS) senses cytosolic DNA and catalyses synthesis of the second messenger cGAMP, which activates the downstream signalling adaptor protein STING, leading to the expression of type I interferons. Hepatitis B virus (HBV) is a small DNA virus, and the cGAS-STING pathway may inhibit HBV RNA synthesis and viral assembly in cell culture, but the exact roles of the cGAS pathway in the restriction of HBV replication in infection systems remain to be elucidated. In this study, replication of HBV was significantly inhibited both in cell culture and in a mouse model when the cGAS-STING pathway was activated by dsDNA or cGAMP. In contrast, the presence of enzymatically inactive cGAS mutant did not influence HBV replication. Moreover, knockdown of cGAS in human peripheral blood monocytes led to a higher level of intracellular HBV DNA. Collectively, our data indicate that the cGAS-STING pathway plays a role in the surveillance of HBV infection and may be exploited for development of novel anti-HBV strategies.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): cGAMP , cGAS and HBV replication.
© 2016 The Authors
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2016-12-16
2024-04-16
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References

  1. Ablasser A., Goldeck M., Cavlar T., Deimling T., Witte G., Röhl I., Hopfner K. P., Ludwig J., Hornung V. 2013; cGAS produces a 2′–5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498:380–384 [View Article][PubMed]
     [Google Scholar]
  2. Atianand M. K., Fitzgerald K. A. 2013; Molecular basis of DNA recognition in the immune system. J Immunol 190:1911–1918 [View Article][PubMed]
     [Google Scholar]
  3. Beck J., Nassal M. 2007; Hepatitis B virus replication. World J Gastroenterol 13:48–64 [View Article][PubMed]
     [Google Scholar]
  4. Cabrerizo M., Bartolomé J., De Sequera P., Caramelo C., Carreño V. 1997; Hepatitis B virus DNA in serum and blood cells of Hepatitis B surface antigen-negative hemodialysis patients and staff. J Am Soc Nephrol 8:1443–1447[PubMed]
     [Google Scholar]
  5. Cai X., Chiu Y. H., Chen Z. J. 2014; The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol Cell 54:289–296 [View Article][PubMed]
     [Google Scholar]
  6. Cavlar T., Ablasser A., Hornung V. 2012; Induction of type I IFNs by intracellular DNA-sensing pathways. Immunol Cell Biol 90:474–482 [View Article][PubMed]
     [Google Scholar]
  7. Civril F., Deimling T., De Oliveira Mann C. C., Ablasser A., Moldt M., Witte G., Hornung V., Hopfner K. P. 2013; Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498:332–337 [View Article][PubMed]
     [Google Scholar]
  8. Dansako H., Ueda Y., Okumura N., Satoh S., Sugiyama M., Mizokami M., Ikeda M., Kato N. 2015; The cyclic GMP-AMP synthetase-STING signaling pathway is required for both the innate immune response against HBV and the suppression of HBV assembly. FEBS J 283:144–156 [View Article][PubMed]
     [Google Scholar]
  9. Diamond M. S., Farzan M. 2013; The broad-spectrum antiviral functions of IFIT and IFITM proteins. Nat Rev Immunol 13:46–57 [View Article][PubMed]
     [Google Scholar]
  10. Gao D., Wu J., Wu Y. T., Du F., Aroh C., Yan N., Sun L., Chen Z. J. 2013a; Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341:903–906 [View Article][PubMed]
     [Google Scholar]
  11. Gao P., Ascano M., Wu Y., Barchet W., Gaffney B. L., Zillinger T., Serganov A. A., Liu Y., Jones R. A. et al. 2013b; Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153:1094–1107 [View Article][PubMed]
     [Google Scholar]
  12. Grimm D., Thimme R., Blum H. E. 2011; Hbv life cycle and novel drug targets. Hepatol Int 5:644–653 [View Article][PubMed]
     [Google Scholar]
  13. Guidotti L. G., Chisari F. V. 2006; Immunobiology and pathogenesis of viral hepatitis. Annu Rev Pathol 1:23–61 [View Article][PubMed]
     [Google Scholar]
  14. Guo H., Jiang D., Ma D., Chang J., Dougherty A. M., Cuconati A., Block T. M., Guo J. T. 2009; Activation of pattern recognition receptor-mediated innate immunity inhibits the replication of Hepatitis B virus in human hepatocyte-derived cells. J Virol 83:847–858 [View Article][PubMed]
     [Google Scholar]
  15. Hao R., He J., Liu X., Gao G., Liu D., Cui L., Yu G., Yu W., Chen Y., Guo D. 2015; Inhibition of Hepatitis B virus gene expression and replication by hepatocyte nuclear factor 6. J Virol 89:4345–4355 [View Article][PubMed]
     [Google Scholar]
  16. Hösel M., Quasdorff M., Wiegmann K., Webb D., Zedler U., Broxtermann M., Tedjokusumo R., Esser K., Arzberger S. et al. 2009; Not interferon, but interleukin-6 controls early gene expression in Hepatitis B virus infection. Hepatology 50:1773–1782 [View Article][PubMed]
     [Google Scholar]
  17. Ishii K. J., Coban C., Kato H., Takahashi K., Torii Y., Takeshita F., Ludwig H., Sutter G., Suzuki K. et al. 2006; A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol 7:40–48 [View Article][PubMed]
     [Google Scholar]
  18. Ishikawa H., Barber G. N. 2008; STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455:674–678 [View Article][PubMed]
     [Google Scholar]
  19. Ishikawa H., Ma Z., Barber G. N. 2009; STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–792 [View Article][PubMed]
     [Google Scholar]
  20. Kranzusch P. J., Lee A. S., Berger J. M., Doudna J. A. 2013; Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity. Cell Rep 3:1362–1368 [View Article][PubMed]
     [Google Scholar]
  21. Kristiansen H., Gad H. H., Eskildsen-Larsen S., Despres P., Hartmann R. 2011; The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activities. J Interferon Cytokine Res 31:41–47 [View Article][PubMed]
     [Google Scholar]
  22. Li X., Shu C., Yi G., Chaton C. T., Shelton C. L., Diao J., Zuo X., Kao C. C., Herr A. B., Li P. 2013; Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization. Immunity 39:1019–1031 [View Article][PubMed]
     [Google Scholar]
  23. Michalak T., Pasquinelli C., Guilhot S., Chisari F. 1994; Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 94:907 [View Article][PubMed]
     [Google Scholar]
  24. Morales D. J., Lenschow D. J. 2013; The antiviral activities of ISG15. J Mol Biol 425:4995–5008 [CrossRef]
     [Google Scholar]
  25. Römling U. 2008; Great times for small molecules: c-di-AMP, a second messenger candidate in Bacteria and Archaea. Sci Signal 1:pe39 [CrossRef]
     [Google Scholar]
  26. Saitoh T., Fujita N., Hayashi T., Takahara K., Satoh T., Lee H., Matsunaga K., Kageyama S., Omori H. et al. 2009; Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc Natl Acad Sci U S A 106:20842–20846 [View Article][PubMed]
     [Google Scholar]
  27. Schneider W. M., Chevillotte M. D., Rice C. M. 2014; Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 32:513–545 [View Article][PubMed]
     [Google Scholar]
  28. Seeger C., Mason W. S. 2000; Hepatitis B virus biology. Microbiol Mol Biol Rev 64:51–68 [View Article][PubMed]
     [Google Scholar]
  29. Stark G. R., Kerr I. M., Williams B. R., Silverman R. H., Schreiber R. D. 1998; How cells respond to interferons. Annu Rev Biochem 67:227–264 [View Article][PubMed]
     [Google Scholar]
  30. Sun W., Li Y., Chen L., Chen H., You F., Zhou X., Zhou Y., Zhai Z., Chen D., Jiang Z. 2009; ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Natl Acad Sci U S A 106:8653–8658 [View Article][PubMed]
     [Google Scholar]
  31. Sun L., Wu J., Du F., Chen X., Chen Z. J. 2013; Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–791 [View Article][PubMed]
     [Google Scholar]
  32. Tamayo R., Pratt J. T., Camilli A. 2007; Roles of cyclic diguanylate in the regulation of bacterial pathogenesis. Annu Rev Microbiol 61:131–148 [View Article][PubMed]
     [Google Scholar]
  33. Tanaka Y., Chen Z. J. 2012; STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci Signal 5:ra20 [View Article][PubMed]
     [Google Scholar]
  34. Trippler M., Meyer zum Büschenfelde K. H., Gerken G. 1999; HBV viral load within subpopulations of peripheral blood mononuclear cells in HBV infection using limiting dilution PCR. J Virol Methods 78:129–147 [View Article][PubMed]
     [Google Scholar]
  35. Wu J., Sun L., Chen X., Du F., Shi H., Chen C., Chen Z. J. 2013; Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339:826–830 [View Article][PubMed]
     [Google Scholar]
  36. Zhang E., Lu M. 2015; Toll-like receptor (TLR)-mediated innate immune responses in the control of Hepatitis B virus (HBV) infection. Med Microbiol Immunol 204:11–20 [View Article][PubMed]
     [Google Scholar]
  37. Zhang X., Shi H., Wu J., Zhang X., Sun L., Chen C., Chen Z. J. 2013; Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol Cell 51:226–235 [View Article][PubMed]
     [Google Scholar]
  38. Zhang X., Wu J., Du F., Xu H., Sun L., Chen Z., Brautigam C. A., Zhang X., Chen Z. J. 2014; The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep 6:421–430 [View Article][PubMed]
     [Google Scholar]
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Inhibition of hepatitis B virus replication by activation of the cGAS-STING pathway
J. Gen. Virol. 97, 3368 (2016); https://doi.org/10.1099/jgv.0.000647
/content/journal/jgv/10.1099/jgv.0.000647
/content/journal/jgv/10.1099/jgv.0.000647
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