Skip to main content

Advertisement

SpringerLink
Log in

Coevolution pays off: Herpesviruses have the license to escape the DNA sensing pathway

  • Review
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Early detection of viral invasion by pattern recognition receptors (PRR) is crucial for the induction of a rapid and efficient immune response. Cytosolic DNA sensors are the most recently described class of PRR, and induce transcription of type I interferons (IFN) and proinflammatory cytokines via the key adaptor protein stimulator of interferon genes (STING). Herpesviruses are a family of large DNA viruses widely known for their immense arsenal of proteins dedicated to manipulating and evading host immune responses. Tantamount to the significant role played by DNA sensors and STING in innate immune responses, herpesviruses have in turn evolved a range of mechanisms targeting virtually every step of this key signaling pathway. Strikingly, some herpesviruses also take advantage of this pathway to promote their own replication. In this review, we will summarize the current understanding of DNA sensing and subsequent induction of signaling and transcription, and showcase the close adaptation of herpesviruses to their host reflected by the myriad of viral proteins dedicated to modulating this critical innate immune pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Davison AJ, Eberle R, Ehlers B, Hayward GS, McGeoch DJ, Minson AC, Pellett PE, Roizman B, Studdert MJ, Thiry E (2009) The order herpesvirales. Arch Virol 154(1):171–177

    CAS  PubMed  Google Scholar 

  2. Pellett P, Roizman B (2007) Herpesviridae: a brief introduction. In: Howley P (ed) Fields virology, 5th edn. Lippincott, Philadelphia, pp 2480–2499

    Google Scholar 

  3. Kutok JL, Wang F (2006) Spectrum of Epstein-Barr virus-associated diseases. Annu Rev Pathol 1:375–404

    CAS  PubMed  Google Scholar 

  4. Roizman B, Taddeo B (2007) The strategy of herpes simplex virus replication and takeover of the host cell. In: Arvin A, Campadelli-Fiume G, Mocarski E et al (eds) Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge University Press, Cambridge, Chap. 13

    Google Scholar 

  5. Mocarski E (2007) Betaherpesvirus genes and their functions. In: Arvin A, Campadelli-Fiume G, Mocarski E et al (eds) Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge University Press, Cambridge, Chap. 15

    Google Scholar 

  6. Patel JR, Heldens J (2005) Equine herpesviruses 1 (EHV-1) and 4 (EHV-4)—epidemiology, disease and immunoprophylaxis: a brief review. Vet J 170(1):14–23

    CAS  PubMed  Google Scholar 

  7. Yates WD (1982) A review of infectious bovine rhinotracheitis, shipping fever pneumonia and viral-bacterial synergism in respiratory disease of cattle. Can J Comp Med 46(3):225–263

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Nauwynck HJ (1997) Functional aspects of Aujeszky’s disease (pseudorabies) viral proteins with relation to invasion, virulence and immunogenicity. Vet Microbiol 55(1–4):3–11

    CAS  PubMed  Google Scholar 

  9. Nair V (2005) Evolution of Marek’s disease—a paradigm for incessant race between the pathogen and the host. Vet J (London, England: 1997) 170(2):175–183

    CAS  Google Scholar 

  10. Reddehase MJ, Lemmermann NAW (2018) Mouse model of cytomegalovirus disease and immunotherapy in the Immunocompromised host: predictions for medical translation that survived the “Test of Time”. Viruses 2018;10(12):693

    CAS  PubMed Central  Google Scholar 

  11. Ablashi D, Agut H, Alvarez-Lafuente R, Clark DA, Dewhurst S, DiLuca D, Flamand L, Frenkel N, Gallo R, Gompels UA, Hollsberg P, Jacobson S, Luppi M, Lusso P, Malnati M, Medveczky P, Mori Y, Pellett PE, Pritchett JC, Yamanishi K, Yoshikawa T (2014) Classification of HHV-6A and HHV-6B as distinct viruses. Arch Virol 159(5):863–870

    CAS  PubMed  Google Scholar 

  12. Mori Y, Yamanishi K (2007) HHV-6A, 6B, and 7: pathogenesis, host response, and clinical disease. In: Arvin A, Campadelli-Fiume G, Mocarski E et al (eds) Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge University Press, Cambridge, Chap. 46

    Google Scholar 

  13. Dittmer DP, Damania B (2013) Kaposi sarcoma associated herpesvirus pathogenesis (KSHV)—an update. Curr Opin Virol 3(3):238–244

    PubMed  PubMed Central  Google Scholar 

  14. Hjalgrim H, Smedby KE, Rostgaard K, Molin D, Hamilton-Dutoit S, Chang ET, Ralfkiaer E, Sundstrom C, Adami HO, Glimelius B, Melbye M (2007) Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma. Cancer Res 67(5):2382–2388

    CAS  PubMed  Google Scholar 

  15. Barton E, Mandal P, Speck SH (2011) Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol 29:351–397

    CAS  PubMed  Google Scholar 

  16. Dittmer DP, Damania B, Sin SH (2015) Animal models of tumorigenic herpesviruses—an update. Curr Opin Virol 14:145–150

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Goldner T, Hewlett G, Ettischer N, Ruebsamen-Schaeff H, Zimmermann H, Lischka P (2011) The novel anticytomegalovirus compound AIC246 (Letermovir) inhibits human cytomegalovirus replication through a specific antiviral mechanism that involves the viral terminase. J Virol 85(20):10884–10893

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lischka P, Hewlett G, Wunberg T, Baumeister J, Paulsen D, Goldner T, Ruebsamen-Schaeff H, Zimmermann H (2010) In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob Agents Chemother 54(3):1290–1297

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Piret J, Drouot E, Boivin G (2017) Antiviral Drug Resistance in Herpesviruses. In: Gotte M, Berghuis A, Matlashewski G, Wainberg M, Sheppard D (eds) Handbook of antimicrobial resistance. Springer, New York, pp 1–32

    Google Scholar 

  20. Vazquez M, LaRussa PS, Gershon AA, Steinberg SP, Freudigman K, Shapiro ED (2001) The effectiveness of the varicella vaccine in clinical practice. N Engl J Med 344(13):955–960

    CAS  PubMed  Google Scholar 

  21. Gao D, Wu J, Wu YT, Du F, Aroh C, Yan N, Sun L, Chen ZJ (2013) Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341(6148):903–906

    CAS  PubMed  Google Scholar 

  22. Sun L, Wu J, Du F, Chen X, Chen ZJ (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339(6121):786–791

    CAS  PubMed  Google Scholar 

  23. Zhang Y, Yeruva L, Marinov A, Prantner D, Wyrick PB, Lupashin V, Nagarajan UM (2014) The DNA sensor, cyclic GMP-AMP synthase, is essential for induction of IFN-beta during Chlamydia trachomatis infection. J Immunol 193(5):2394–2404

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G, Rohl I, Hopfner KP, Ludwig J, Hornung V (2013) cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498(7454):380–384

    CAS  PubMed  PubMed Central  Google Scholar 

  25. West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, Bestwick M, Duguay BA, Raimundo N, MacDuff DA, Kaech SM, Smiley JR, Means RE, Iwasaki A, Shadel GS (2015) Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520(7548):553–557

    PubMed  PubMed Central  Google Scholar 

  26. Yang H, Wang H, Ren J, Chen Q, Chen ZJ (2017) cGAS is essential for cellular senescence. Proc Natl Acad Sci USA 114(23):E4612–E4620

    CAS  PubMed  Google Scholar 

  27. Liu H, Zhang H, Wu X, Ma D, Wu J, Wang L, Jiang Y, Fei Y, Zhu C, Tan R, Jungblut P, Pei G, Dorhoi A, Yan Q, Zhang F, Zheng R, Liu S, Liang H, Liu Z, Yang H, Chen J, Wang P, Tang T, Peng W, Hu Z, Xu Z, Huang X, Wang J, Li H, Zhou Y, Liu F, Yan D, Kaufmann SHE, Chen C, Mao Z, Ge B (2018) Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 563(7729):131–136

    CAS  PubMed  Google Scholar 

  28. Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, Du F, Ren J, Wu YT, Grishin NV, Chen ZJ (2015) Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347(6227):aaa2630

    PubMed  Google Scholar 

  29. Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, Latz E, Hornung V (2013) Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503(7477):530–534

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Bridgeman A, Maelfait J, Davenne T, Partridge T, Peng Y, Mayer A, Dong T, Kaever V, Borrow P, Rehwinkel J (2015) Viruses transfer the antiviral second messenger cGAMP between cells. Science 349(6253):1228–1232

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Gentili M, Kowal J, Tkach M, Satoh T, Lahaye X, Conrad C, Boyron M, Lombard B, Durand S, Kroemer G, Loew D, Dalod M, Thery C, Manel N (2015) Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science 349(6253):1232–1236

    CAS  PubMed  Google Scholar 

  32. Ishikawa H, Barber GN (2011) The STING pathway and regulation of innate immune signaling in response to DNA pathogens. Cell Mol Life Sci 68(7):1157–1165

    CAS  PubMed  Google Scholar 

  33. Tsuchida T, Zou J, Saitoh T, Kumar H, Abe T, Matsuura Y, Kawai T, Akira S (2010) The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA. Immunity 33(5):765–776

    CAS  PubMed  Google Scholar 

  34. Zhang J, Hu MM, Wang YY, Shu HB (2012) TRIM32 protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination. J Biol Chem 287(34):28646–28655

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang Q, Liu X, Cui Y, Tang Y, Chen W, Li S, Yu H, Pan Y, Wang C (2014) The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING. Immunity 41(6):919–933

    CAS  PubMed  Google Scholar 

  36. Prabakaran T, Bodda C, Krapp C, Zhang BC, Christensen MH, Sun C, Reinert L, Cai Y, Jensen SB, Skouboe MK, Nyengaard JR, Thompson CB, Lebbink RJ, Sen GC, van Loo G, Nielsen R, Komatsu M, Nejsum LN, Jakobsen MR, Gyrd-Hansen M, Paludan SR (2018) Attenuation of cGAS-STING signaling is mediated by a p62/SQSTM1-dependent autophagy pathway activated by TBK1. EMBO J 37(8): e97858

    PubMed  PubMed Central  Google Scholar 

  37. Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T, Lee H, Matsunaga K, Kageyama S, Omori H, Noda T, Yamamoto N, Kawai T, Ishii K, Takeuchi O, Yoshimori T, Akira S (2009) Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc Natl Acad Sci USA 106(49):20842–20846

    CAS  PubMed  Google Scholar 

  38. Abe T, Barber GN (2014) Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-kappaB activation through TBK1. J Virol 88(10):5328–5341

    PubMed  PubMed Central  Google Scholar 

  39. Stempel M, Chan B, Juranić Lisnić V, Krmpotić A, Hartung J, Paludan SR, Füllbrunn N, Lemmermann NA, Brinkmann MM (2019) The herpesviral antagonist m152 reveals differential activation of STING-dependent IRF and NF-κB signaling and STING’s dual role during MCMV infection. EMBO J. https://doi.org/10.15252/embj.2018100983

    Article  PubMed  PubMed Central  Google Scholar 

  40. Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB, Sharma S, Sirois CM, Jin T, Latz E, Xiao TS, Fitzgerald KA, Paludan SR, Bowie AG (2010) IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol 11(11):997–1004

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Dell’Oste V, Gatti D, Gugliesi F, De Andrea M, Bawadekar M, Lo Cigno I, Biolatti M, Vallino M, Marschall M, Gariglio M, Landolfo S (2014) Innate nuclear sensor IFI16 translocates into the cytoplasm during the early stage of in vitro human cytomegalovirus infection and is entrapped in the egressing virions during the late stage. J Virol 88(12):6970–6982

    PubMed  PubMed Central  Google Scholar 

  42. Orzalli MH, Broekema NM, Diner BA, Hancks DC, Elde NC, Cristea IM, Knipe DM (2015) cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection. Proc Natl Acad Sci USA 112(14):E1773–E1781

    CAS  PubMed  Google Scholar 

  43. Diner BA, Lum KK, Toettcher JE, Cristea IM (2016) Viral DNA sensors IFI16 and Cyclic GMP-AMP synthase possess distinct functions in regulating viral gene expression, immune defenses, and apoptotic responses during herpesvirus infection. MBio 7(6):e01553–e01516

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Jonsson KL, Laustsen A, Krapp C, Skipper KA, Thavachelvam K, Hotter D, Egedal JH, Kjolby M, Mohammadi P, Prabakaran T, Sorensen LK, Sun C, Jensen SB, Holm CK, Lebbink RJ, Johannsen M, Nyegaard M, Mikkelsen JG, Kirchhoff F, Paludan SR, Jakobsen MR (2017) IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP. Nat Commun 8:14391

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Almine JF, O’Hare CA, Dunphy G, Haga IR, Naik RJ, Atrih A, Connolly DJ, Taylor J, Kelsall IR, Bowie AG, Beard PM, Unterholzner L (2017) IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes. Nat Commun 8:14392

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lugrin J, Martinon F (2018) The AIM2 inflammasome: sensor of pathogens and cellular perturbations. Immunol Rev 281(1):99–114

    CAS  PubMed  Google Scholar 

  47. Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ (2011) The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat Immunol 12(10):959–965

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, Lu Y, Miyagishi M, Kodama T, Honda K, Ohba Y, Taniguchi T (2007) DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448(7152):501–505

    CAS  PubMed  Google Scholar 

  49. Zhang X, Brann TW, Zhou M, Yang J, Oguariri RM, Lidie KB, Imamichi H, Huang D-W, Lempicki RA, Baseler MW, Veenstra TD, Young HA, Lane HC, Imamichi T (2011) Cutting edge: Ku70 Is a novel cytosolic DNA sensor that induces type III rather than type I IFN. J Immunol 186(8):4541–4545

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ishikawa H, Ma Z, Barber GN (2009) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461(7265):788–792

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Johnson KE, Bottero V, Flaherty S, Dutta S, Singh VV, Chandran B (2014) IFI16 restricts HSV-1 replication by accumulating on the hsv-1 genome, repressing HSV-1 gene expression, and directly or indirectly modulating histone modifications. PLoS Pathog 10(11):e1004503

    PubMed  PubMed Central  Google Scholar 

  52. Ansari MA, Dutta S, Veettil MV, Dutta D, Iqbal J, Kumar B, Roy A, Chikoti L, Singh VV, Chandran B (2015) Herpesvirus genome recognition induced acetylation of nuclear IFI16 Is essential for its cytoplasmic translocation, inflammasome and IFN-beta responses. PLoS Pathog 11(7):e1005019

    PubMed  PubMed Central  Google Scholar 

  53. Gariano GR, Dell’Oste V, Bronzini M, Gatti D, Luganini A, De Andrea M, Gribaudo G, Gariglio M, Landolfo S (2012) The intracellular DNA sensor IFI16 gene acts as restriction factor for human cytomegalovirus replication. PLoS Pathog 8(1):e1002498

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Gray EE, Winship D, Snyder JM, Child SJ, Geballe AP, Stetson DB (2016) The AIM2-like receptors are dispensable for the interferon response to intracellular DNA. Immunity 45(2):255–266

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Biolatti M, Dell’Oste V, Pautasso S, Gugliesi F, von Einem J, Krapp C, Jakobsen MR, Borgogna C, Gariglio M, De Andrea M, Landolfo S (2018) Human cytomegalovirus tegument protein pp65 (pUL83) dampens type I interferon production by inactivating the DNA sensor cGAS without affecting STING. J Virol 92:(6)

    Google Scholar 

  56. Paijo J, Doring M, Spanier J, Grabski E, Nooruzzaman M, Schmidt T, Witte G, Messerle M, Hornung V, Kaever V, Kalinke U (2016) cGAS senses human cytomegalovirus and induces Type I interferon responses in human monocyte-derived cells. PLoS Pathog 12(4):e1005546

    PubMed  PubMed Central  Google Scholar 

  57. Lio CW, McDonald B, Takahashi M, Dhanwani R, Sharma N, Huang J, Pham E, Benedict CA, Sharma S (2016) cGAS-STING signaling regulates initial innate control of cytomegalovirus infection. J Virol 90(17):7789–7797

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Schoggins JW, MacDuff DA, Imanaka N, Gainey MD, Shrestha B, Eitson JL, Mar KB, Richardson RB, Ratushny AV, Litvak V, Dabelic R, Manicassamy B, Aitchison JD, Aderem A, Elliott RM, Garcia-Sastre A, Racaniello V, Snijder EJ, Yokoyama WM, Diamond MS, Virgin HW, Rice CM (2014) Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505(7485):691–695

    CAS  PubMed  Google Scholar 

  59. Ma Z, Jacobs SR, West JA, Stopford C, Zhang Z, Davis Z, Barber GN, Glaunsinger BA, Dittmer DP, Damania B (2015) Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc Natl Acad Sci USA 112(31):E4306–E4315

    CAS  PubMed  Google Scholar 

  60. Zhang G, Chan B, Samarina N, Abere B, Weidner-Glunde M, Buch A, Pich A, Brinkmann MM, Schulz TF (2016) Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS. Proc Natl Acad Sci USA 113(8):E1034–E1043

    CAS  PubMed  Google Scholar 

  61. Huang J, You H, Su C, Li Y, Chen S, Zheng C (2018) Herpes simplex virus 1 tegument protein VP22 abrogates cGAS/STING-mediated antiviral innate immunity. J Virol 92:(15)

    Google Scholar 

  62. Zhang J, Zhao J, Xu S, Li J, He S, Zeng Y, Xie L, Xie N, Liu T, Lee K, Seo GJ, Chen L, Stabell AC, Xia Z, Sawyer SL, Jung J, Huang C, Feng P (2018) Species-specific deamidation of cGAS by herpes simplex virus UL37 protein facilitates viral replication. Cell Host Microbe 24(2):234–248 e235

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Su C, Zheng C (2017) Herpes simplex virus 1 abrogates the cGAS/STING-mediated cytosolic DNA-sensing pathway via its virion host shutoff protein, UL41. J Virol 91(6):JVI-02414

    Google Scholar 

  64. Huang ZF, Zou HM, Liao BW, Zhang HY, Yang Y, Fu YZ, Wang SY, Luo MH, Wang YY (2018) Human Cytomegalovirus protein UL31 Inhibits DNA sensing of cGAS to mediate immune evasion. Cell Host Microbe 24(1):69–80 e64

    CAS  PubMed  Google Scholar 

  65. Wu JJ, Li W, Shao Y, Avey D, Fu B, Gillen J, Hand T, Ma S, Liu X, Miley W, Konrad A, Neipel F, Sturzl M, Whitby D, Li H, Zhu F (2015) Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein. Cell Host Microbe 18(3):333–344

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Orzalli MH, DeLuca NA, Knipe DM (2012) Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein. Proc Natl Acad Sci USA 109(44):E3008–E3017

    CAS  PubMed  Google Scholar 

  67. Cuchet-Lourenco D, Anderson G, Sloan E, Orr A, Everett RD (2013) The viral ubiquitin ligase ICP0 is neither sufficient nor necessary for degradation of the cellular DNA sensor IFI16 during herpes simplex virus 1 infection. J Virol 87(24):13422–13432

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Li T, Chen J, Cristea IM (2013) Human cytomegalovirus tegument protein pUL83 inhibits IFI16-mediated DNA sensing for immune evasion. Cell Host Microbe 14(5):591–599

    CAS  PubMed  Google Scholar 

  69. Deschamps T, Kalamvoki M (2017) Evasion of the STING DNA-sensing pathway by VP11/12 of herpes simplex virus 1. J Virol 91(16):JVI-00535

    Google Scholar 

  70. Kim JE, Kim YE, Stinski MF, Ahn JH, Song YJ (2017) Human cytomegalovirus IE2 86 kda protein induces STING degradation and inhibits cGAMP-Mediated IFN-beta Induction. Front Microbiol 8:1854

    PubMed  PubMed Central  Google Scholar 

  71. Fu YZ, Su S, Gao YQ, Wang PP, Huang ZF, Hu MM, Luo WW, Li S, Luo MH, Wang YY, Shu HB (2017) Human Cytomegalovirus tegument protein UL82 inhibits STING-Mediated signaling to evade antiviral immunity. Cell Host Microbe 21(2):231–243

    CAS  PubMed  Google Scholar 

  72. Choi HJ, Park A, Kang S, Lee E, Lee TA, Ra EA, Lee J, Lee S, Park B (2018) Human cytomegalovirus-encoded US9 targets MAVS and STING signaling to evade type I interferon immune responses. Nat Commun 9(1):125

    PubMed  PubMed Central  Google Scholar 

  73. Kumari P, Saha I, Narayanan A, Narayanan S, Takaoka A, Kumar NS, Tailor P, Kumar H (2017) Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways. Cell Death Dis 8(10):e3078

    PubMed  PubMed Central  Google Scholar 

  74. Sun C, Schattgen SA, Pisitkun P, Jorgensen JP, Hilterbrand AT, Wang LJ, West JA, Hansen K, Horan KA, Jakobsen MR, O’Hare P, Adler H, Sun R, Ploegh HL, Damania B, Upton JW, Fitzgerald KA, Paludan SR (2015) Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection. J Immunol 194(4):1819–1831

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ma Y, Jin H, Valyi-Nagy T, Cao Y, Yan Z, He B (2012) Inhibition of TANK binding kinase 1 by herpes simplex virus 1 facilitates productive infection. J Virol 86(4):2188–2196

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Manivanh R, Mehrbach J, Knipe DM, Leib DA (2017) Role of herpes simplex virus 1 γ34.5 in the regulation of IRF3 signaling. J Virol 91(23):e01156–e01117

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Christensen MH, Jensen SB, Miettinen JJ, Luecke S, Prabakaran T, Reinert LS, Mettenleiter T, Chen ZJ, Knipe DM, Sandri-Goldin RM, Enquist LW, Hartmann R, Mogensen TH, Rice SA, Nyman TA, Matikainen S, Paludan SR (2016) HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression. EMBO J 35(13):1385–1399

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Liu X, Main D, Ma Y, He B (2018) Herpes Simplex Virus 1 Inhibits TANK-Binding Kinase 1 through Formation of the Us11-Hsp90 Complex. J Virol 92(14):e00402–e00418

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kang HR, Cheong WC, Park JE, Ryu S, Cho HJ, Youn H, Ahn JH, Song MJ (2014) Murine gammaherpesvirus 68 encoding open reading frame 11 targets TANK binding kinase 1 to negatively regulate the host type I interferon response. J Virol 88(12):6832–6846

    PubMed  PubMed Central  Google Scholar 

  80. Zhang D, Su C, Zheng C (2016) Herpes Simplex virus 1 serine protease VP24 blocks the DNA-sensing signal pathway by abrogating activation of interferon regulatory factor 3. J Virol 90(12):5824–5829

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Sen N, Sommer M, Che X, White K, Ruyechan WT, Arvin AM (2010) Varicella-zoster virus immediate-early protein 62 blocks interferon regulatory factor 3 (IRF3) phosphorylation at key serine residues: a novel mechanism of IRF3 inhibition among herpesviruses. J Virol 84(18):9240–9253

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Vandevenne P, Lebrun M, El Mjiyad N, Ote I, Di Valentin E, Habraken Y, Dortu E, Piette J, Sadzot-Delvaux C (2011) The varicella-zoster virus ORF47 kinase interferes with host innate immune response by inhibiting the activation of IRF3. PLoS One 6(2):e16870

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhu H, Zheng C, Xing J, Wang S, Li S, Lin R, Mossman KL (2011) Varicella-zoster virus immediate-early protein ORF61 abrogates the IRF3-mediated innate immune response through degradation of activated IRF3. J Virol 85(21):11079–11089

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Lin R, Genin P, Mamane Y, Sgarbanti M, Battistini A, Harrington WJ Jr, Barber GN, Hiscott J (2001) HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators. Oncogene 20(7):800–811

    CAS  PubMed  Google Scholar 

  85. Lefort S, Soucy-Faulkner A, Grandvaux N, Flamand L (2007) Binding of Kaposi’s sarcoma-associated herpesvirus K-bZIP to interferon-responsive factor 3 elements modulates antiviral gene expression. J Virol 81(20):10950–10960

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang JT, Doong SL, Teng SC, Lee CP, Tsai CH, Chen MR (2009) Epstein-Barr virus BGLF4 kinase suppresses the interferon regulatory factor 3 signaling pathway. J Virol 83(4):1856–1869

    CAS  PubMed  Google Scholar 

  87. Hwang S, Kim KS, Flano E, Wu TT, Tong LM, Park AN, Song MJ, Sanchez DJ, O’Connell RM, Cheng G, Sun R (2009) Conserved herpesviral kinase promotes viral persistence by inhibiting the IRF-3-mediated type I interferon response. Cell Host Microbe 5(2):166–178

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Jaworska J, Gravel A, Fink K, Grandvaux N, Flamand L (2007) Inhibition of transcription of the beta interferon gene by the human herpesvirus 6 immediate-early 1 protein. J Virol 81(11):5737–5748

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Ye R, Su C, Xu H, Zheng C (2017) Herpes simplex Virus 1 ubiquitin-specific protease UL36 abrogates NF-kappaB activation in DNA sensing signal pathway. J Virol 91(5):e02417–e02416

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Whitmer T, Malouli D, Uebelhoer LS, DeFilippis VR, Fruh K, Verweij MC (2015) The ORF61 protein encoded by Simian varicella virus and Varicella-Zoster virus inhibits NF-kappaB signaling by interfering with IkappaBalpha degradation. J Virol 89(17):8687–8700

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Xu H, Su C, Pearson A, Mody CH, Zheng C (2017) Herpes Simplex Virus 1 UL24 Abrogates the DNA Sensing Signal Pathway by Inhibiting NF-kappaB Activation. J Virol 91(7):e00025–e00017

    PubMed  PubMed Central  Google Scholar 

  92. Zhang J, Wang S, Wang K, Zheng C (2013) Herpes simplex virus 1 DNA polymerase processivity factor UL42 inhibits TNF-alpha-induced NF-kappaB activation by interacting with p65/RelA and p50/NF-kappaB1. Med Microbiol Immunol 202(4):313–325

    CAS  PubMed  Google Scholar 

  93. Mathers C, Schafer X, Martinez-Sobrido L, Munger J (2014) The human cytomegalovirus UL26 protein antagonizes NF-kappaB activation. J Virol 88(24):14289–14300

    PubMed  PubMed Central  Google Scholar 

  94. Wang K, Ni L, Wang S, Zheng C (2014) Herpes simplex virus 1 protein kinase US3 hyperphosphorylates p65/RelA and dampens NF-kappaB activation. J Virol 88(14):7941–7951

    PubMed  PubMed Central  Google Scholar 

  95. Wang S, Wang K, Lin R, Zheng C (2013) Herpes simplex virus 1 serine/threonine kinase US3 hyperphosphorylates IRF3 and inhibits beta interferon production. J Virol 87(23):12814–12827

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Xing J, Ni L, Wang S, Wang K, Lin R, Zheng C (2013) Herpes simplex virus 1-encoded tegument protein VP16 abrogates the production of beta interferon (IFN) by inhibiting NF-kappaB activation and blocking IFN regulatory factor 3 to recruit its coactivator CBP. J Virol 87(17):9788–9801

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Chan B, Goncalves Magalhaes V, Lemmermann NAW, Juranic Lisnic V, Stempel M, Bussey KA, Reimer E, Podlech J, Lienenklaus S, Reddehase MJ, Jonjic S, Brinkmann MM (2017) The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-kappaB mediated transcription. PLoS Pathog 13(5):e1006382

    PubMed  PubMed Central  Google Scholar 

  98. Steain M, Slobedman B, Abendroth A (2010) Experimental models to study varicella-zoster virus infection of neurons. Curr Top Microbiol Immunol 342:211–228

    CAS  PubMed  Google Scholar 

  99. Markus A, Lebenthal-Loinger I, Yang IH, Kinchington PR, Goldstein RS (2015) An in vitro model of latency and reactivation of varicella zoster virus in human stem cell-derived neurons. PLoS Pathog 11(6):e1004885

    PubMed  PubMed Central  Google Scholar 

  100. Ishikawa H, Barber GN (2008) STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455(7213):674–678

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Jin L, Waterman PM, Jonscher KR, Short CM, Reisdorph NA, Cambier JC (2008) MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class II and mediates transduction of apoptotic signals. Mol Cell Biol 28(16):5014–5026

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 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 USA 106(21):8653–8658

    CAS  PubMed  Google Scholar 

  103. Zhong B, Yang Y, Li S, Wang YY, Li Y, Diao F, Lei C, He X, Zhang L, Tien P, Shu HB (2008) The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29(4):538–550

    CAS  PubMed  Google Scholar 

  104. Tanaka M, Kato A, Satoh Y, Ide T, Sagou K, Kimura K, Hasegawa H, Kawaguchi Y (2012) Herpes simplex virus 1 VP22 regulates translocation of multiple viral and cellular proteins and promotes neurovirulence. J Virol 86(9):5264–5277

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhao J, Zeng Y, Xu S, Chen J, Shen G, Yu C, Knipe D, Yuan W, Peng J, Xu W, Zhang C, Xia Z, Feng P (2016) A Viral Deamidase targets the helicase domain of RIG-I to block RNA-induced activation. Cell Host Microbe 20(6):770–784

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Esclatine A, Taddeo B, Evans L, Roizman B (2004) The herpes simplex virus 1 UL41 gene-dependent destabilization of cellular RNAs is selective and may be sequence-specific. Proc Natl Acad Sci USA 101(10):3603–3608

    CAS  PubMed  Google Scholar 

  107. Johnson KE, Chikoti L, Chandran B (2013) Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J Virol 87(9):5005–5018

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Kalamvoki M, Roizman B (2014) HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation. Proc Natl Acad Sci USA 111(5):E611–E617

    CAS  PubMed  Google Scholar 

  109. Browne EP, Shenk T (2003) Human cytomegalovirus UL83-coded pp65 virion protein inhibits antiviral gene expression in infected cells. Proc Natl Acad Sci USA 100(20):11439–11444

    CAS  PubMed  Google Scholar 

  110. Abate DA, Watanabe S, Mocarski ES (2004) Major human cytomegalovirus structural protein pp65 (ppUL83) prevents interferon response factor 3 activation in the interferon response. J Virol 78(20):10995–11006

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Cristea IM, Moorman NJ, Terhune SS, Cuevas CD, O’Keefe ES, Rout MP, Chait BT, Shenk T (2010) Human cytomegalovirus pUL83 stimulates activity of the viral immediate-early promoter through its interaction with the cellular IFI16 protein. J Virol 84(15):7803–7814

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Biolatti M, Dell’Oste V, Pautasso S, von Einem J, Marschall M, Plachter B, Gariglio M, De Andrea M, Landolfo S (2016) Regulatory interaction between the cellular restriction factor IFI16 and viral pp65 (pUL83) modulates viral gene expression and IFI16 protein stability. J Virol 90(18):8238–8250

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Weidner-Glunde M, Mariggio G, Schulz TF (2017) Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen: replicating and shielding viral DNA during viral persistence. J Virol 2017 91(14):e01083–e01016

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Taylor RT, Bresnahan WA (2005) Human cytomegalovirus immediate-early 2 gene expression blocks virus-induced beta interferon production. J Virol 79(6):3873–3877

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Taylor RT, Bresnahan WA (2006) Human cytomegalovirus IE86 attenuates virus- and tumor necrosis factor alpha-induced NFkappaB-dependent gene expression. J Virol 80(21):10763–10771

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Shen W, Westgard E, Huang L, Ward MD, Osborn JL, Chau NH, Collins L, Marcum B, Koach MA, Bibbs J, Semmes OJ, Kerry JA (2008) Nuclear trafficking of the human cytomegalovirus pp71 (ppUL82) tegument protein. Virology 376(1):42–52

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Lodoen M, Ogasawara K, Hamerman JA, Arase H, Houchins JP, Mocarski ES, Lanier LL (2003) NKG2D-mediated natural killer cell protection against cytomegalovirus is impaired by viral gp40 modulation of retinoic acid early inducible 1 gene molecules. J Exp Med 197(10):1245–1253

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Krmpotic A, Messerle M, Crnkovic-Mertens I, Polic B, Jonjic S, Koszinowski UH (1999) The immunoevasive function encoded by the mouse cytomegalovirus gene m152 protects the virus against T cell control in vivo. J Exp Med 190(9):1285–1296

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Ziegler H, Thale R, Lucin P, Muranyi W, Flohr T, Hengel H, Farrell H, Rawlinson W, Koszinowski UH (1997) A mouse cytomegalovirus glycoprotein retains MHC class I complexes in the ERGIC/cis-Golgi compartments. Immunity 6(1):57–66

    CAS  PubMed  Google Scholar 

  120. Fink A, Renzaho A, Reddehase MJ, Lemmermann NA (2013) The p36 isoform of murine cytomegalovirus m152 protein suffices for mediating innate and adaptive immune evasion. Viruses 5(12):3171–3191

    PubMed  PubMed Central  Google Scholar 

  121. Krmpotic A, Busch DH, Bubic I, Gebhardt F, Hengel H, Hasan M, Scalzo AA, Koszinowski UH, Jonjic S (2002) MCMV glycoprotein gp40 confers virus resistance to CD8 + T cells and NK cells in vivo. Nat Immunol 3(6):529–535

    CAS  PubMed  Google Scholar 

  122. Tanaka Y, Chen ZJ (2012) STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci Signal 5(214):ra20

    PubMed  PubMed Central  Google Scholar 

  123. Chou J, Chen JJ, Gross M, Roizman B (1995) Association of a M(r) 90,000 phosphoprotein with protein kinase PKR in cells exhibiting enhanced phosphorylation of translation initiation factor eIF-2 alpha and premature shutoff of protein synthesis after infection with gamma 134.5- mutants of herpes simplex virus 1. Proc Natl Acad Sci USA 92(23):10516–10520

    CAS  PubMed  Google Scholar 

  124. Chou J, Roizman B (1992) The gamma 1(34.5) gene of herpes simplex virus 1 precludes neuroblastoma cells from triggering total shutoff of protein synthesis characteristic of programed cell death in neuronal cells. Proc Natl Acad Sci USA 89(8):3266–3270

    CAS  PubMed  Google Scholar 

  125. Boname JM, May JS, Stevenson PG (2005) Murine gammaherpesvirus 68 open reading frame 11 encodes a nonessential virion component. J Virol 79(5):3163–3168

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Wang S, Wang K, Li J, Zheng C (2013) Herpes simplex virus 1 ubiquitin-specific protease UL36 inhibits beta interferon production by deubiquitinating TRAF3. J Virol 87(21):11851–11860

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Lin SF, Robinson DR, Miller G, Kung HJ (1999) Kaposi’s sarcoma-associated herpesvirus encodes a bZIP protein with homology to BZLF1 of Epstein-Barr virus. J Virol 73(3):1909–1917

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the SMART BIOTECS alliance between the Technische Universität Braunschweig and the Leibniz Universität Hannover, funded by the Ministry of Science and Culture (MWK) of Lower Saxony, Germany, and the Deutsche Forschungsgemeinschaft (DFG), BR3432/3-1.

Author information

Authors and Affiliations

  1. Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Brunswick, Germany

    Markus Stempel & Melanie M. Brinkmann

  2. Viral Genomics Group, Institute for Respiratory Health, University of Western Australia, Nedlands, Australia

    Baca Chan

  3. Institute of Genetics, Technische Universität Braunschweig, Brunswick, Germany

    Melanie M. Brinkmann

Authors
  1. Markus Stempel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Baca Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melanie M. Brinkmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Melanie M. Brinkmann.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Edited by Matthias J. Reddehase.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Special Issue on Immunological Imprinting during Chronic Viral Infection.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stempel, M., Chan, B. & Brinkmann, M.M. Coevolution pays off: Herpesviruses have the license to escape the DNA sensing pathway. Med Microbiol Immunol 208, 495–512 (2019). https://doi.org/10.1007/s00430-019-00582-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-019-00582-0

Keywords

Search

Navigation