Citation: Yue Si, Haijun Zhang, Ziqing Zhou, Xudong Zhu, Yongheng Yang, He Liu, Liang Zhang, Linfeng Cheng, Kerong Wang, Wei Ye, Xin Lv, Xijing Zhang, Wugang Hou, Gang Zhao, Yingfeng Lei, Fanglin Zhang, Hongwei Ma. RIPK3 promotes hantaviral replication by restricting JAK-STAT signaling without triggering necroptosis .VIROLOGICA SINICA, 2023, 38(5) : 741-754.  http://dx.doi.org/10.1016/j.virs.2023.08.006

RIPK3 promotes hantaviral replication by restricting JAK-STAT signaling without triggering necroptosis

  • Hantaan virus (HTNV) is a rodent-borne virus that causes hemorrhagic fever with renal syndrome (HFRS), resulting in a high mortality rate of 15%. Interferons (IFNs) play a critical role in the anti-hantaviral immune response, and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFN-stimulated genes (ISGs) through the Janus kinase-signal transducer and activator of transcription 1 (JAK-STAT) pathway. However, the tremendous amount of IFNs produced during late infection could not restrain HTNV replication, and the mechanism remains unclear. Here, we demonstrated that receptor-interacting protein kinase 3 (RIPK3), a crucial molecule that mediates necroptosis, was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation. RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection, with RIPK3 identified as a key modulator of viral replication. RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication, without affecting the expression of pattern recognition receptors (PRRs) or the production of type I IFNs. Conversely, exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication. RIPK3-/- mice also maintained a robust ability to clear HTNV with enhanced innate immune responses. Mechanistically, we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain (PKD) of RIPK3 but not its kinase activity. Overall, these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.

  • 加载中
  • 10.1016j.virs.2023.08.006-EMS.docx
    1. Bedient, L., Pokharel, S.M., Chiok, K.R., Mohanty, I., Beach, S.S., Miura, T.A., Bose, S., 2020. Lytic Cell Death Mechanisms in Human Respiratory Syncytial Virus-Infected Macrophages:Roles of Pyroptosis and Necroptosis. Viruses 12.

    2. Bian, P., Ye, C., Zheng, X., Luo, C., Yang, J., Li, M., Wang, Y., Yang, J., Zhou, Y., Zhang, F., Lian, J., Zhang, Y., Jia, Z., Lei, Y., 2020. RIPK3 Promotes JEV Replication in Neurons via Downregulation of IFI44L. Frontiers in microbiology 11, 368.

    3. Christgen, S., Tweedell, R.E., Kanneganti, T.D., 2022. Programming inflammatory cell death for therapy. Pharmacology & therapeutics 232, 108010.

    4. Daffis, S., Szretter, K.J., Schriewer, J., Li, J., Youn, S., Errett, J., Lin, T.Y., Schneller, S., Zust, R., Dong, H., Thiel, V., Sen, G.C., Fensterl, V., Klimstra, W.B., Pierson, T.C., Buller, R.M., Gale, M., Jr., Shi, P.Y., Diamond, M.S., 2010. 2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature 468, 452-456.

    5. Dai, J., Pan, W., Wang, P., 2011. ISG15 facilitates cellular antiviral response to dengue and west nile virus infection in vitro. Virology journal 8, 468.

    6. Dermentzaki, G., Politi, K.A., Lu, L., Mishra, V., Pérez-Torres, E.J., Sosunov, A.A., McKhann, G.M., 2nd, Lotti, F., Shneider, N.A., Przedborski, S., 2019. Deletion of Ripk3 Prevents Motor Neuron Death In Vitro but not In Vivo. eNeuro 6.

    7. Downey, J., Pernet, E., Coulombe, F., Allard, B., Meunier, I., Jaworska, J., Qureshi, S., Vinh, D.C., Martin, J.G., Joubert, P., Divangahi, M., 2017. RIPK3 interacts with MAVS to regulate type I IFN-mediated immunity to Influenza A virus infection. PLoS pathogens 13, e1006326.

    8. Ermonval, M., Baychelier, F., Tordo, N., 2016. What Do We Know about How Hantaviruses Interact with Their Different Hosts? Viruses 8.

    9. Fuchs, J., Hölzer, M., Schilling, M., Patzina, C., Schoen, A., Hoenen, T., Zimmer, G., Marz, M., Weber, F., Müller, M.A., Kochs, G., 2017. Evolution and Antiviral Specificities of Interferon-Induced Mx Proteins of Bats against Ebola, Influenza, and Other RNA Viruses. Journal of virology 91.

    10. Gaba, A., Xu, F., Lu, Y., Park, H.S., Liu, G., Zhou, Y., 2019. The NS1 Protein of Influenza A Virus Participates in Necroptosis by Interacting with MLKL and Increasing Its Oligomerization and Membrane Translocation. Journal of virology 93.

    11. Giannakopoulos, N.V., Arutyunova, E., Lai, C., Lenschow, D.J., Haas, A.L., Virgin, H.W., 2009. ISG15 Arg151 and the ISG15-conjugating enzyme UbE1L are important for innate immune control of Sindbis virus. Journal of virology 83, 1602-1610.

    12. Golden, J.W., Hammerbeck, C.D., Mucker, E.M., Brocato, R.L., 2015. Animal Models for the Study of Rodent-Borne Hemorrhagic Fever Viruses:Arenaviruses and Hantaviruses. BioMed research international 2015, 793257.

    13. Gordon, S., Martinez, F.O., 2010. Alternative activation of macrophages:mechanism and functions. Immunity 32, 593-604.

    14. Gowen, B.B., Hickerson, B.T., 2017. Hemorrhagic fever of bunyavirus etiology:disease models and progress towards new therapies. Journal of microbiology (Seoul, Korea) 55, 183-195.

    15. Haller, O., Kochs, G., Weber, F., 2007. Interferon, Mx, and viral countermeasures. Cytokine & growth factor reviews 18, 425-433.

    16. Handke, W., Oelschlegel, R., Franke, R., Krüger, D.H., Rang, A., 2009. Hantaan virus triggers TLR3-dependent innate immune responses. Journal of immunology (Baltimore, Md.:1950) 182, 2849-2858.

    17. Hansen, L.W., Jacob, A., Yang, W.L., Bolognese, A.C., Prince, J., Nicastro, J.M., Coppa, G.F., Wang, P., 2018. Deficiency of receptor-interacting protein kinase 3 (RIPK3) attenuates inflammation and organ injury in neonatal sepsis. Journal of pediatric surgery 53, 1699-1705.

    18. Hardestam, J., Klingström, J., Mattsson, K., Lundkvist, A., 2005. HFRS causing hantaviruses do not induce apoptosis in confluent Vero E6 and A-549 cells. Journal of medical virology 76, 234-240.

    19. Heap, R.E., Marín-Rubio, J.L., Peltier, J., Heunis, T., Dannoura, A., Moore, A., Trost, M., 2021. Proteomics characterisation of the L929 cell supernatant and its role in BMDM differentiation. Life science alliance 4.

    20. Hsiang, T.Y., Zhao, C., Krug, R.M., 2009. Interferon-induced ISG15 conjugation inhibits influenza A virus gene expression and replication in human cells. Journal of virology 83, 5971-5977.

    21. Hsiao, N.W., Chen, J.W., Yang, T.C., Orloff, G.M., Wu, Y.Y., Lai, C.H., Lan, Y.C., Lin, C.W., 2010. ISG15 over-expression inhibits replication of the Japanese encephalitis virus in human medulloblastoma cells. Antiviral research 85, 504-511.

    22. Hussain, M., Zimmermann, V., van Wijk, S.J.L., Fulda, S., 2018. Mouse lung fibroblasts are highly susceptible to necroptosis in a reactive oxygen species-dependent manner. Biochemical pharmacology 153, 242-247.

    23. Jiang, H., Du, H., Wang, L.M., Wang, P.Z., Bai, X.F., 2016. Hemorrhagic Fever with Renal Syndrome:Pathogenesis and Clinical Picture. Frontiers in cellular and infection microbiology 6, 1.

    24. Kaiser, W.J., Sridharan, H., Huang, C., Mandal, P., Upton, J.W., Gough, P.J., Sehon, C.A., Marquis, R.W., Bertin, J., Mocarski, E.S., 2013. Toll-like receptor 3-mediated necrosis via TRIF, RIP3, and MLKL. The Journal of biological chemistry 288, 31268-31279.

    25. Kariwa, H., Yoshimatsu, K., Arikawa, J., 2007. Hantavirus infection in East Asia. Comp Immunol Microbiol Infect Dis 30, 341-356.

    26. Karlberg, H., Tan, Y.J., Mirazimi, A., 2011. Induction of caspase activation and cleavage of the viral nucleocapsid protein in different cell types during Crimean-Congo hemorrhagic fever virus infection. The Journal of biological chemistry 286, 3227-3234.

    27. Kimura, T., Katoh, H., Kayama, H., Saiga, H., Okuyama, M., Okamoto, T., Umemoto, E., Matsuura, Y., Yamamoto, M., Takeda, K., 2013. Ifit1 inhibits Japanese encephalitis virus replication through binding to 5' capped 2'-O unmethylated RNA. Journal of virology 87, 9997-10003.

    28. Koehler, H., Cotsmire, S., Zhang, T., Balachandran, S., Upton, J.W., Langland, J., Kalman, D., Jacobs, B.L., Mocarski, E.S., 2021. Vaccinia virus E3 prevents sensing of Z-RNA to block ZBP1-dependent necroptosis. Cell host & microbe 29, 1266-1276.e1265.

    29. Laskowski, R.A., 2001. PDBsum:summaries and analyses of PDB structures. Nucleic acids research 29, 221-222.

    30. Lee, A.J., Ashkar, A.A., 2018. The Dual Nature of Type I and Type II Interferons. Frontiers in immunology 9, 2061.

    31. Li, B., Wang, X., Yu, M., Yang, P., Wang, W., 2020. G6PD, bond by miR-24, regulates mitochondrial dysfunction and oxidative stress in phenylephrine-induced hypertrophic cardiomyocytes. Life sciences 260, 118378.

    32. Lu, D.H., Jiang, H., Lian, J.Q., 2021. Hantavirus Infection during Pregnancy. Virologica Sinica 36, 345-353.

    33. Ma, H., Han, P., Ye, W., Chen, H., Zheng, X., Cheng, L., Zhang, L., Yu, L., Wu, X., Xu, Z., Lei, Y., Zhang, F., 2017a. The Long Noncoding RNA NEAT1 Exerts Antihantaviral Effects by Acting as Positive Feedback for RIG-I Signaling. Journal of virology 91.

    34. Ma, H.W., Ye, W., Chen, H.S., Nie, T.J., Cheng, L.F., Zhang, L., Han, P.J., Wu, X.A., Xu, Z.K., Lei, Y.F., Zhang, F.L., 2017b. In-Cell Western Assays to Evaluate Hantaan Virus Replication as a Novel Approach to Screen Antiviral Molecules and Detect Neutralizing Antibody Titers. Frontiers in cellular and infection microbiology 7, 269.

    35. Ma, R., Zhang, X., Shu, J., Liu, Z., Sun, W., Hou, S., Lv, Y., Ying, Q., Wang, F., Jin, X., Liu, R., Wu, X., 2021. Nlrc3 Knockout Mice Showed Renal Pathological Changes After HTNV Infection. Frontiers in immunology 12, 692509.

    36. Malakhova, O.A., Zhang, D.E., 2008. ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response. The Journal of biological chemistry 283, 8783-8787.

    37. Martens, S., Bridelance, J., Roelandt, R., Vandenabeele, P., Takahashi, N., 2021. MLKL in cancer:more than a necroptosis regulator. Cell death and differentiation 28, 1757-1772.

    38. Meng, Y., Sandow, J.J., Czabotar, P.E., Murphy, J.M., 2021. The regulation of necroptosis by post-translational modifications. Cell death and differentiation 28, 861-883.

    39. Mesev, E.V., LeDesma, R.A., Ploss, A., 2019. Decoding type I and III interferon signalling during viral infection. Nature microbiology 4, 914-924.

    40. Newton, K., Dugger, D.L., Wickliffe, K.E., Kapoor, N., de Almagro, M.C., Vucic, D., Komuves, L., Ferrando, R.E., French, D.M., Webster, J., Roose-Girma, M., Warming, S., Dixit, V.M., 2014. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science (New York, N.Y.) 343, 1357-1360.

    41. Nguyen, L.N., Kanneganti, T.D., 2022. PANoptosis in Viral Infection:The Missing Puzzle Piece in the Cell Death Field. Journal of molecular biology 434, 167249.

    42. Ning, T., Wang, L., Liu, S., Ma, J., Nie, J., Huang, W., Li, X., Li, Y., Wang, Y., 2021. Monitoring Neutralization Property Change of Evolving Hantaan and Seoul Viruses with a Novel Pseudovirus-Based Assay. Virologica Sinica 36, 104-112.

    43. Orinska, Z., Bulanova, E., Budagian, V., Metz, M., Maurer, M., Bulfone-Paus, S., 2005. TLR3-induced activation of mast cells modulates CD8+ T-cell recruitment. Blood 106, 978-987.

    44. Park, K., Kim, W.K., Lee, S.H., Kim, J., Lee, J., Cho, S., Lee, G.Y., No, J.S., Lee, K.H., Song, J.W., 2021. A novel genotype of Hantaan orthohantavirus harbored by Apodemus agrarius chejuensis as a potential etiologic agent of hemorrhagic fever with renal syndrome in Republic of Korea. PLoS neglected tropical diseases 15, e0009400.

    45. Pasparakis, M., Vandenabeele, P., 2015. Necroptosis and its role in inflammation. Nature 517, 311-320.

    46. Perng, Y.C., Lenschow, D.J., 2018. ISG15 in antiviral immunity and beyond. Nat Rev Microbiol 16, 423-439.

    47. Pinto, A.K., Williams, G.D., Szretter, K.J., White, J.P., Proença-Módena, J.L., Liu, G., Olejnik, J., Brien, J.D., Ebihara, H., Mühlberger, E., Amarasinghe, G., Diamond, M.S., Boon, A.C., 2015. Human and Murine IFIT1 Proteins Do Not Restrict Infection of Negative-Sense RNA Viruses of the Orthomyxoviridae, Bunyaviridae, and Filoviridae Families. Journal of virology 89, 9465-9476.

    48. Raftery, M.J., Abdelaziz, M.O., Hofmann, J., Schönrich, G., 2018. Hantavirus-Driven PD-L1/PD-L2 Upregulation:An Imperfect Viral Immune Evasion Mechanism. Frontiers in immunology 9, 2560.

    49. Raftery, M.J., Lalwani, P., Lütteke, N., Kobak, L., Giese, T., Ulrich, R.G., Radosa, L., Krüger, D.H., Schönrich, G., 2020. Replication in the Mononuclear Phagocyte System (MPS) as a Determinant of Hantavirus Pathogenicity. Frontiers in cellular and infection microbiology 10, 281.

    50. Reynaud, J.M., Kim, D.Y., Atasheva, S., Rasalouskaya, A., White, J.P., Diamond, M.S., Weaver, S.C., Frolova, E.I., Frolov, I., 2015. IFIT1 Differentially Interferes with Translation and Replication of Alphavirus Genomes and Promotes Induction of Type I Interferon. PLoS pathogens 11, e1004863.

    51. Saleh, D., Najjar, M., Zelic, M., Shah, S., Nogusa, S., Polykratis, A., Paczosa, M.K., Gough, P.J., Bertin, J., Whalen, M., Fitzgerald, K.A., Slavov, N., Pasparakis, M., Balachandran, S., Kelliher, M., Mecsas, J., Degterev, A., 2017. Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-β Synthesis Induced by Lipopolysaccharide. Journal of immunology (Baltimore, Md.:1950) 198, 4435-4447.

    52. Salentin, S., Schreiber, S., Haupt, V.J., Adasme, M.F., Schroeder, M., 2015. PLIP:fully automated protein-ligand interaction profiler. Nucleic acids research 43, W443-447.

    53. 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.

    54. Schnittler, H.J., Feldmann, H., 2003. Viral hemorrhagic fever——a vascular disease? Thromb Haemost 89, 967-972.

    55. Scholz, S., Baharom, F., Rankin, G., Maleki, K.T., Gupta, S., Vangeti, S., Pourazar, J., Discacciati, A., Höijer, J., Bottai, M., Björkström, N.K., Rasmuson, J., Evander, M., Blomberg, A., Ljunggren, H.G., Klingström, J., Ahlm, C., Smed-Sörensen, A., 2017. Human hantavirus infection elicits pronounced redistribution of mononuclear phagocytes in peripheral blood and airways. PLoS pathogens 13, e1006462.

    56. Shrum, B., Anantha, R.V., Xu, S.X., Donnelly, M., Haeryfar, S.M., McCormick, J.K., Mele, T., 2014. A robust scoring system to evaluate sepsis severity in an animal model. BMC research notes 7, 233.

    57. Solà-Riera, C., García, M., Ljunggren, H.G., Klingström, J., 2020. Hantavirus inhibits apoptosis by preventing mitochondrial membrane potential loss through up-regulation of the pro-survival factor BCL-2. PLoS pathogens 16, e1008297.

    58. Steere, A.C., Green, J., Hutchinson, G.J., Rahn, D.W., Pachner, A.R., Schoen, R.T., Sigal, L.H., Taylor, E., Malawista, S.E., 1987. Treatment of Lyme disease. Zentralblatt fur Bakteriologie, Mikrobiologie, und Hygiene. Series A, Medical microbiology, infectious diseases, virology, parasitology 263, 352-356.

    59. Sulzbacher, M.M., Sulzbacher, L.M., Passos, F.R., Bilibio, B.L.E., de Oliveira, K., Althaus, W.F., Frizzo, M.N., Ludwig, M.S., Da Cruz, I.B.M., Heck, T.G., 2022. Adapted Murine Sepsis Score:Improving the Research in Experimental Sepsis Mouse Model. BioMed research international 2022, 5700853.

    60. Tariq, M., Kim, D.M., 2022. Hemorrhagic Fever with Renal Syndrome:Literature Review, Epidemiology, Clinical Picture and Pathogenesis. Infection & chemotherapy 54, 1-19.

    61. Tartey, S., Takeuchi, O., 2017. Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells. International reviews of immunology 36, 57-73.

    62. Villarino, A.V., Kanno, Y., O'Shea, J.J., 2017. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol 18, 374-384.

    63. Wang, K., Ma, H., Liu, H., Ye, W., Li, Z., Cheng, L., Zhang, L., Lei, Y., Shen, L., Zhang, F., 2019. The Glycoprotein and Nucleocapsid Protein of Hantaviruses Manipulate Autophagy Flux to Restrain Host Innate Immune Responses. Cell reports 27, 2075-2091.e2075.

    64. Wang, P.Z., Li, Z.D., Yu, H.T., Zhang, Y., Wang, W., Jiang, W., Bai, X.F., 2012. Elevated serum concentrations of inflammatory cytokines and chemokines in patients with haemorrhagic fever with renal syndrome. The Journal of international medical research 40, 648-656.

    65. Weigert, M., Binks, A., Dowson, S., Leung, E.Y.L., Athineos, D., Yu, X., Mullin, M., Walton, J.B., Orange, C., Ennis, D., Blyth, K., Tait, S.W.G., McNeish, I.A., 2017. RIPK3 promotes adenovirus type 5 activity. Cell death & disease 8, 3206.

    66. Wu, J., Zhu, K., Luo, X., Han, Y., Zhang, B., Wang, Z., Dong, S., Zou, X., Chen, X., Liu, H., Wu, T., Zheng, Z., Xie, Y., Zhao, J., Liu, Y., Wen, Z., Liu, D., Wang, Y., Zheng, S., Huang, X., Jing, C., Yang, G., 2020. PM(2.5) promotes replication of VSV by ubiquitination degradation of phospho-IRF3 in A549 cells. Toxicology in vitro:an international journal published in association with BIBRA 62, 104698.

    67. Xu, Z., Wei, L., Wang, L., Wang, H., Jiang, S., 2002. The in vitro and in vivo protective activity of monoclonal antibodies directed against Hantaan virus:potential application for immunotherapy and passive immunization. Biochemical and biophysical research communications 298, 552-558.

    68. Yan, Y., Zhang, D., Zhou, P., Li, B., Huang, S.Y., 2017. HDOCK:a web server for protein-protein and protein-DNA/RNA docking based on a hybrid strategy. Nucleic acids research 45, W365-w373.

    69. Yang, Y., Li, M., Ma, Y., Ye, W., Si, Y., Zheng, X., Liu, H., Cheng, L., Zhang, L., Zhang, H., Zhang, X., Lei, Y., Shen, L., Zhang, F., Ma, H., 2022. LncRNA NEAT1 Potentiates SREBP2 Activity to Promote Inflammatory Macrophage Activation and Limit Hantaan Virus Propagation. Frontiers in microbiology 13, 849020.

    70. Ye, W., Xu, Y., Wang, Y., Dong, Y., Xi, Q., Cao, M., Yu, L., Zhang, L., Cheng, L., Wu, X., Xu, Z., Lei, Y., Zhang, F., 2015. Hantaan virus can infect human keratinocytes and activate an interferon response through the nuclear translocation of IRF-3. Infection, genetics and evolution:journal of molecular epidemiology and evolutionary genetics in infectious diseases 29, 146-155.

    71. Yiang, G.T., Chen, Y.H., Chou, P.L., Chang, W.J., Wei, C.W., Yu, Y.L., 2013. The NS3 protease and helicase domains of Japanese encephalitis virus trigger cell death via caspase‑dependent and ‑independent pathways. Molecular medicine reports 7, 826-830.

    72. Yin, H., Wang, Z., Yang, S., Zheng, X., Bao, Y., Lin, W., Huang, C., Qiu, L., 2022. Taurine inhibits necroptosis helps to alleviate inflammatory and injury induced by Klebsiella infection. Veterinary immunology and immunopathology 250, 110444.

    73. Zhan, Q., Jeon, J., Li, Y., Huang, Y., Xiong, J., Wang, Q., Xu, T.L., Li, Y., Ji, F.H., Du, G., Zhu, M.X., 2022. CAMK2/CaMKII activates MLKL in short-term starvation to facilitate autophagic flux. Autophagy 18, 726-744.

    74. Zhang, Y., Liu, B., Ma, Y., Yi, J., Zhang, C., Zhang, Y., Xu, Z., Wang, J., Yang, K., Yang, A., Zhuang, R., Jin, B., 2014. Hantaan virus infection induces CXCL10 expression through TLR3, RIG-I, and MDA-5 pathways correlated with the disease severity. Mediators of inflammation 2014, 697837.

    75. Zhang, Y., Ma, R., Wang, Y., Sun, W., Yang, Z., Han, M., Han, T., Wu, X.A., Liu, R., 2021. Viruses Run:The Evasion Mechanisms of the Antiviral Innate Immunity by Hantavirus. Frontiers in microbiology 12, 759198.

    76. Zhao, Q., Yu, X., Zhang, H., Liu, Y., Zhang, X., Wu, X., Xie, Q., Li, M., Ying, H., Zhang, H., 2017. RIPK3 Mediates Necroptosis during Embryonic Development and Postnatal Inflammation in Fadd-Deficient Mice. Cell reports 19, 798-808.

    77. Zheng, M., Williams, E.P., Malireddi, R.K.S., Karki, R., Banoth, B., Burton, A., Webby, R., Channappanavar, R., Jonsson, C.B., Kanneganti, T.D., 2020. Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection. The Journal of biological chemistry 295, 14040-14052.

  • 加载中

Article Metrics

Article views(2156) PDF downloads(18) Cited by()

Related
Proportional views

    RIPK3 promotes hantaviral replication by restricting JAK-STAT signaling without triggering necroptosis

      Corresponding author: Yingfeng Lei, yflei@fmmu.edu.cn
      Corresponding author: Fanglin Zhang, flzhang@fmmu.edu.cn
      Corresponding author: Hongwei Ma, mahongwei0720@sina.com
    • a. Department of Microbiology, School of Basic Medicine, Air Force Medical University, Xi'an, 710032, China;
    • b. Department of Neurology, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China;
    • c. Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Key Laboratory of Aerospace Medicine of Ministry of Education, Air Force Medical University, Xi'an, 710032, China;
    • d. Department of Anesthesiology & Critical Care Medicine, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China;
    • e. The College of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China

    Abstract: Hantaan virus (HTNV) is a rodent-borne virus that causes hemorrhagic fever with renal syndrome (HFRS), resulting in a high mortality rate of 15%. Interferons (IFNs) play a critical role in the anti-hantaviral immune response, and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFN-stimulated genes (ISGs) through the Janus kinase-signal transducer and activator of transcription 1 (JAK-STAT) pathway. However, the tremendous amount of IFNs produced during late infection could not restrain HTNV replication, and the mechanism remains unclear. Here, we demonstrated that receptor-interacting protein kinase 3 (RIPK3), a crucial molecule that mediates necroptosis, was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation. RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection, with RIPK3 identified as a key modulator of viral replication. RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication, without affecting the expression of pattern recognition receptors (PRRs) or the production of type I IFNs. Conversely, exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication. RIPK3-/- mice also maintained a robust ability to clear HTNV with enhanced innate immune responses. Mechanistically, we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain (PKD) of RIPK3 but not its kinase activity. Overall, these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.

    Reference (77) Relative (20)

    目录

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return