Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지
DOI QR코드

DOI QR Code

Dengue Virus 2 NS2B Targets MAVS and IKKε to Evade the Antiviral Innate Immune Response

  • Ying Nie (The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine) ;
  • Dongqing Deng (Department of Parasitology; Provincial Key Laboratory of Modern Pathogen Biology, College of Basic Medical Sciences, Guizhou Medical University) ;
  • Lumin Mou (Department of Parasitology; Provincial Key Laboratory of Modern Pathogen Biology, College of Basic Medical Sciences, Guizhou Medical University) ;
  • Qizhou Long (Department of Parasitology; Provincial Key Laboratory of Modern Pathogen Biology, College of Basic Medical Sciences, Guizhou Medical University) ;
  • Jinzhi Chen (Department of Parasitology; Provincial Key Laboratory of Modern Pathogen Biology, College of Basic Medical Sciences, Guizhou Medical University) ;
  • Jiahong Wu (Department of Parasitology; Provincial Key Laboratory of Modern Pathogen Biology, College of Basic Medical Sciences, Guizhou Medical University)
  • Received : 2022.10.05
  • Accepted : 2023.02.03
  • Published : 2023.05.28
Download PDF
⟨ Previous Next ⟩

Abstract

Dengue virus (DENV) is a widespread arbovirus. To efficiently establish infection, DENV evolves multiple strategies to hijack the host innate immune response. Herein, we examined the inhibitory effects of DENV serotype 2 (DENV2) nonstructural proteins on RIG-I-directed antiviral immune response. We found that DENV2 NS2A, NS2B, NS4A, and NS4B significantly inhibited RIG-I-mediated IFN-β promoter activation. The roles of NS2B in RIG-I-directed antiviral immune response are unknown. Our study further showed that NS2B could dose-dependently suppress RIG-I/MAVS-induced activation of IFN-β promoter. Consistently, NS2B significantly decreased RIG-I- and MAVS-induced transcription of IFNB1, ISG15, and ISG56. Mechanistically, NS2B was found to interact with MAVS and IKKε to impair RIG-I-directed antiviral response. Our findings demonstrated a previously uncharacterized function of NS2B in RIG-I-mediated antiviral response, making it a promising drug target for anti-DENV treatments.

Keywords

Acknowledgement

This study was supported by Guizhou Provincial Science and Technology Projects (Qiankehejichu [2019]1021), Youth Science and Technology Talents Growth project of the Guizhou Provincial Education Department (Qianjiaohe KY Zi [2018] 213), the National Natural Science Foundation of China (31960166).

References

  1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. 2013. The global distribution and burden of dengue. Nature 496: 504-507. https://doi.org/10.1038/nature12060
  2. Bhatt P, Sabeena SP, Varma M, Arunkumar G. 2021. Current understanding of the pathogenesis of Dengue Virus infection. Curr. Microbiol. 78: 17-32. https://doi.org/10.1007/s00284-020-02284-w
  3. Harapan H, Michie A, Sasmono RT, Imrie A. 2020. Dengue: a minireview. Viruses 12: 829.
  4. Park J, Kim J, Jang YS. 2022. Current status and perspectives on vaccine development against dengue virus infection. J. Microbiol. 60: 247-254. https://doi.org/10.1007/s12275-022-1625-y
  5. Wilder-Smith A, Ooi EE, Horstick O, Wills B. 2019. Dengue. Lancet 393: 350-363. https://doi.org/10.1016/S0140-6736(18)32560-1
  6. Ngono AE, Shresta S. 2018. Immune response to Dengue and Zika. Ann. Rev. Immunol. 36: 279-308. https://doi.org/10.1146/annurev-immunol-042617-053142
  7. Nasirudeen AM, Wong HH, Thien P, Xu S, Lam KP, Liu DX. 2011. RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection. PLoS Negl. Trop. Dis. 5: e926.
  8. Uno N, Ross TM. 2018. Dengue virus and the host innate immune response. Emerg. Microbes Infect. 7: 167.
  9. Seth RB, Sun L, Ea CK, Chen ZJ. 2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122: 669-682. https://doi.org/10.1016/j.cell.2005.08.012
  10. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB. 2005. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19: 727-740. https://doi.org/10.1016/j.molcel.2005.08.014
  11. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, et al. 2005. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437: 1167-1172. https://doi.org/10.1038/nature04193
  12. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, et al. 2005. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat. Immunol. 6: 981-988. https://doi.org/10.1038/ni1243
  13. Fang R, Jiang Q, Zhou X, Wang C, Guan Y, Tao J, et al. 2017. MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner. PLoS Pathog. 13: e1006720.
  14. Schoggins JW, Rice CM. 2011. Interferon-stimulated genes and their antiviral effector functions. Curr. Opin. Virol. 1: 519-525. https://doi.org/10.1016/j.coviro.2011.10.008
  15. Schoggins JW. 2018. Recent advances in antiviral interferon-stimulated gene biology. F1000Res 7: 309.
  16. Dalrymple NA, Cimica V, Mackow ER. 2015. Dengue Virus NS proteins inhibit RIG-I/MAVS signaling by blocking TBK1/IRF3 phosphorylation: Dengue Virus serotype 1 NS4A Is a unique interferon-regulating virulence determinant. mBio 6: e00553-00515.
  17. He Z, Zhu X, Wen W, Yuan J, Hu Y, Chen J, et al. 2016. Dengue Virus subverts host innate immunity by targeting adaptor protein MAVS. J. Virol. 90: 7219-7230. https://doi.org/10.1128/JVI.00221-16
  18. Wahaab A, Mustafa BE, Hameed M, Stevenson NJ, Anwar MN, Liu K, et al. 2021. Potential role of flavivirus NS2B-NS3 proteases in viral pathogenesis and anti-flavivirus drug discovery employing animal cells and models: a review. Viruses 14: 44.
  19. Anglero-Rodriguez YI, Pantoja P, Sariol CA. 2014. Dengue virus subverts the interferon induction pathway via NS2B/3 protease-IκB kinase epsilon interaction. Clin. Vaccine Immunol. : CVI. 21: 29-38. https://doi.org/10.1128/CVI.00500-13
  20. Yu CY, Chang TH, Liang JJ, Chiang RL, Lee YL, Liao CL, et al. 2012. Dengue virus targets the adaptor protein MITA to subvert host innate immunity. PLoS Pathog. 8: e1002780.
  21. Aguirre S, Luthra P, Sanchez-Aparicio MT, Maestre AM, Patel J, Lamothe F, et al. 2017. Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection. Nat. Microbiol. 2: 17037.
  22. Aguirre S, Maestre AM, Pagni S, Patel JR, Savage T, Gutman D, et al. 2012. DENV inhibits type I IFN production in infected cells by cleaving human STING. PLoS Pathog. 8: e1002934.
  23. Munoz-Jordan JL, Sanchez-Burgos GG, Laurent-Rolle M, Garcia-Sastre A. 2003. Inhibition of interferon signaling by dengue virus. Proc. Natl. Acad. Sci. USA 100: 14333-14338. https://doi.org/10.1073/pnas.2335168100
  24. Ashour J, Laurent-Rolle M, Shi PY, Garcia-Sastre A. 2009. NS5 of dengue virus mediates STAT2 binding and degradation. J. Virol. 83: 5408-5418. https://doi.org/10.1128/JVI.02188-08
  25. Mazzon M, Jones M, Davidson A, Chain B, Jacobs M. 2009. Dengue virus NS5 inhibits interferon-alpha signaling by blocking signal transducer and activator of transcription 2 phosphorylation. J. Infect. Dis. 200: 1261-1270. https://doi.org/10.1086/605847
  26. Morrison J, Laurent-Rolle M, Maestre AM, Rajsbaum R, Pisanelli G, Simon V, et al. 2013. Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling. PLoS Pathog. 9: e1003265.
  27. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, et al. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5: 730-737. https://doi.org/10.1038/ni1087
  28. Nie Y, Ran Y, Zhang HY, Huang ZF, Pan ZY, Wang SY, et al. 2017. GPATCH3 negatively regulates RLR-mediated innate antiviral responses by disrupting the assembly of VISA signalosome. PLoS Pathog. 13: e1006328.
  29. Li WW, Nie Y, Yang Y, Ran Y, Luo WW, Xiong MG, et al. 2020. Ubiquitination of TLR3 by TRIM3 signals its ESCRT-mediated trafficking to the endolysosomes for innate antiviral response. Proc. Natil. Acad. Sci. USA 117: 23707-23716. https://doi.org/10.1073/pnas.2002472117
  30. Ren Z, Ding T, Zuo Z, Xu Z, Deng J, Wei Z. 2020. Regulation of MAVS expression and signaling function in the antiviral innate immune response. Front. Immunol. 11: 1030.
  31. Niyomrattanakit P, Winoyanuwattikun P, Chanprapaph S, Angsuthanasombat C, Panyim S, Katzenmeier G. 2004. Identification of residues in the dengue virus type 2 NS2B cofactor that are critical for NS3 protease activation. J. Virol. 78: 13708-13716. https://doi.org/10.1128/JVI.78.24.13708-13716.2004
  32. Liu S, Chen J, Cai X, Wu J, Chen X, Wu YT, et al. 2013. MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades. eLife 2: e00785.
  33. Xu H, He X, Zheng H, Huang LJ, Hou F, Yu Z, et al. 2014. Structural basis for the prion-like MAVS filaments in antiviral innate immunity. eLife 3: e01489.
  34. Liu S, Cai X, Wu J, Cong Q, Chen X, Li T, et al. 2015. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347: aaa2630.
  35. Sharma A, Kontodimas K, Bosmann M. 2021. The MAVS Immune recognition pathway in viral infection and sepsis. Antioxid Redox Signal. 35: 1376-1392. https://doi.org/10.1089/ars.2021.0167
  36. Chen Y, Shi Y, Wu J, Qi N. 2021. MAVS: A two-sided CARD Mediating antiviral innate immune signaling and regulating immune homeostasis. Front. Microbiol. 12: 744348.
  37. Ma J, Ketkar H, Geng T, Lo E, Wang L, Xi J, et al. 2018. Zika virus non-structural protein 4A blocks the RLR-MAVS signaling. Front. Microbiol. 9: 1350.
  38. Li W, Li N, Dai S, Hou G, Guo K, Chen X, et al. 2019. Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA. FASEB J. 33: 9929-9944. https://doi.org/10.1096/fj.201900260R
  39. Hu Y, Dong X, He Z, Wu Y, Zhang S, Lin J, et al. 2019. Zika virus antagonizes interferon response in patients and disrupts RIG-I-MAVS interaction through its CARD-TM domains. Cell Biosci. 9: 46.
  40. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. 2005. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc. Natl. Acad. Sci. USA 102: 17717-17722. https://doi.org/10.1073/pnas.0508531102
  41. Bellecave P, Sarasin-Filipowicz M, Donze O, Kennel A, Gouttenoire J, Meylan E, et al. 2010. Cleavage of mitochondrial antiviral signaling protein in the liver of patients with chronic hepatitis C correlates with a reduced activation of the endogenous interferon system. Hepatology 51: 1127-1136. https://doi.org/10.1002/hep.23426
  42. Bender S, Reuter A, Eberle F, Einhorn E, Binder M, Bartenschlager R. 2015. Activation of type I and III interferon response by mitochondrial and peroxisomal MAVS and inhibition by hepatitis C virus. PLoS Pathog. 11: e1005264.
  43. Ferreira AR, Magalhaes AC, Camoes F, Gouveia A, Vieira M, Kagan JC, et al. 2016. Hepatitis C virus NS3-4A inhibits the peroxisomal MAVS-dependent antiviral signalling response. J. Cell. Mol. Med. 20: 750-757. https://doi.org/10.1111/jcmm.12801
  44. Zhou P, Li Y, Liu A, Zhang Q, Wu W, Jin H, et al. 2022. Tembusu virus nonstructural protein 2B antagonizes type I interferon production by targeting MAVS for degradation. J. Virol. 96: e0081622.