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The TET3 inflammasome senses unique long HSV-1 proteins for virus particle budding from the nucleus

Cellular & Molecular Immunology volume 21, pages 1322–1334 (2024)Cite this article

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Abstract

Inflammasomes play important roles in resisting infections caused by various pathogens. HSV-1 is a highly contagious virus among humans. The process by which HSV-1 particles bud from the nucleus is unique to herpes viruses, but the specific mechanism is still unclear. Here, we screened genes involved in HSV-1 replication. We found that TET3 plays an essential role in HSV-1 infection. TET3 recognizes the UL proteins of HSV-1 and, upon activation, can directly bind to caspase-1 to activate an ASC-independent inflammasome in the nucleus. The subsequent cleavage of GSDMD in the nucleus is crucial for the budding of HSV-1 particles from the nucleus. Inhibiting the perforation ability of GSDMD on the nuclear membrane can significantly reduce the maturation and spread of HSV-1. Our results may provide a new approach for the treatment of HSV-1 in the future.

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References

  1. Fu J, Wu H. Structural Mechanisms of NLRP3 Inflammasome Assembly and Activation. Annu Rev Immunol. 2023;41:301–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for noncanonical inflammasome signaling. Nature. 2015;526:666–71.

    Article  CAS  PubMed  Google Scholar 

  3. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660–5.

    Article  CAS  PubMed  Google Scholar 

  4. Zhu F, Ma J, Li W, Liu Q, Qin X, Qian Y, et al. The orphan receptor Nur77 binds cytoplasmic LPS to activate the noncanonical NLRP3 inflammasome. Immunity. 2023;56:753–67.e758.

    Article  CAS  PubMed  Google Scholar 

  5. Kofoed EM, Vance RE. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature. 2011;477:592–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science. 2013;341:1246–9.

    Article  CAS  PubMed  Google Scholar 

  7. Megli CJ, Coyne CB. Infections at the maternal-fetal interface: an overview of pathogenesis and defense. Nat Rev Microbiol. 2022;20:67–82.

    Article  CAS  PubMed  Google Scholar 

  8. Walker FC, Sridhar PR, Baldridge MT. Differential roles of interferons in innate responses to mucosal viral infections. Trends Immunol. 2021;42:1009–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Johnson KE, Chikoti L, Chandran B. Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and the NLRP3 inflammasome. J Virol. 2013;87:5005–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang M, Covar J, Zhang NY, Chen W, Marshall B, Mo J, et al. Virus spread and immune response following anterior chamber inoculation of HSV-1 lacking the Beclin-binding domain (BBD). J Neuroimmunol. 2013;260:82–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bigalke JM, Heuser T, Nicastro D, Heldwein EE. Membrane deformation and scission by the HSV-1 nuclear egress complex. Nat Commun. 2014;5:4131.

    Article  CAS  PubMed  Google Scholar 

  12. Johnson DC, Baines JD. Herpesviruses remodel host membranes for virus egress. Nat Rev Microbiol. 2011;9:382–94.

    Article  CAS  PubMed  Google Scholar 

  13. Ravindran MS, Bagchi P, Cunningham CN, Tsai B. Opportunistic intruders: how viruses orchestrate ER functions to infect cells. Nat Rev Microbiol. 2016;14:407–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Romero-Brey I, Bartenschlager R. Endoplasmic Reticulum: The Favorite Intracellular Niche for Viral Replication and Assembly. Viruses. 2016;8:160.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature. 2019;571:489–99.

    Article  CAS  PubMed  Google Scholar 

  16. Lo YMD, Han DSC, Jiang P, Chiu RWK. Epigenetics, fragmentomics, and topology of cell-free DNA in liquid biopsies. Science 2021;372:eaaw3616.

    Article  CAS  PubMed  Google Scholar 

  17. Gu TP, Guo F, Yang H, Wu HP, Xu GF, Liu W, et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature. 2011;477:606–10.

    Article  CAS  PubMed  Google Scholar 

  18. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011;333:1303–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shen Q, Zhang Q, Shi Y, Shi Q, Jiang Y, Gu Y, et al. Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation. Nature. 2018;554:123–7.

    Article  CAS  PubMed  Google Scholar 

  20. Xue S, Liu C, Sun X, Li W, Zhang C, Zhou X, et al. TET3 Inhibits Type I IFN Production Independent of DNA Demethylation. Cell Rep. 2016;16:1096–105.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015;525:389–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34:267–73.

    Article  CAS  PubMed  Google Scholar 

  23. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim A, Choi SJ, Song GG, Kim JH, Jung JH. Characterization of virus-mediated autoimmunity and the consequences for pathological process in patients with systemic lupus erythematosus. Clin Rheumatol. 2023;42:2799–809.

    Article  PubMed  Google Scholar 

  25. van Gent M, Chiang JJ, Muppala S, Chiang C, Azab W, Kattenhorn L, et al. The US3 Kinase of Herpes Simplex Virus Phosphorylates the RNA Sensor RIG-I To Suppress Innate Immunity. J Virol. 2022;96:e0151021.

    Article  PubMed  Google Scholar 

  26. Wang W, Hu D, Wu C, Feng Y, Li A, Liu W, et al. STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection. PLoS Pathog. 2020;16:e1008335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mohnke J, Stark I, Fischer M, Fischer PM, Schlosser A, Grothey A, et al. pUL36 Deubiquitinase Activity Augments Both the Initiation and the Progression of Lytic Herpes Simplex Virus Infection in IFN-Primed Cells. J Virol. 2022;96:e0096322.

    Article  PubMed  Google Scholar 

  28. Packard JE, Williams MR, Fromuth DP, Dembowski JA. Proliferating cell nuclear antigen inhibitors block distinct stages of herpes simplex virus infection. PLoS Pathog. 2023;19:e1011539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Klupp BG, Mettenleiter TC. The Knowns and Unknowns of Herpesvirus Nuclear Egress. Annu Rev Virol. 2023;10:305–23.

    Article  CAS  PubMed  Google Scholar 

  30. Calbay O, Padia R, Akter M, Sun L, Li B, Qian N, et al. ASC/inflammasome-independent pyroptosis in ovarian cancer cells through translational augmentation of caspase-1. iScience. 2023;26:108408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao E. A Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science. 2013;341:1250–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fu R, Zhao L, Guo Y, Qin X, Xu W, Cheng X et al. AIM2 inflammasome: A potential therapeutic target in ischemic stroke. Clin Immunol. 2024;259:109881.

  33. Devant P, Kagan JC. Molecular mechanisms of gasdermin D pore-forming activity. Nat Immunol. 2023;24:1064–75.

    Article  CAS  PubMed  Google Scholar 

  34. Martin BN, Wang C, Willette-Brown J, Herjan T, Gulen MF, Zhou H, et al. IKKα negatively regulates ASC-dependent inflammasome activation. Nat Commun. 2014;5:4977.

    Article  CAS  PubMed  Google Scholar 

  35. Smatlik N, Drexler S, K, Burian M, Röcken M, Yazdi AS. ASC Speck Formation after Inflammasome Activation in Primary Human Keratinocytes. Oxid Med Cell Longev. 2021;2021:7914829.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Peng X, Na R, Zhou W, Meng X, Yang Y, Amini S, et al. Nuclear translocation of Gasdermin D sensitizes colorectal cancer to chemotherapy in a pyroptosis-independent manner. Oncogene. 2022;41:5092–106.

    Article  CAS  PubMed  Google Scholar 

  37. Wang L, Fu H, Nanayakkara G, Li Y, Shao Y, Johnson C, et al. Novel extracellular and nuclear caspase-1 and inflammasomes propagate inflammation and regulate gene expression: a comprehensive database mining study. J Hematol Oncol. 2016;9:122.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Xia S, Zhang Z, Magupalli VG, Pablo JL, Dong Y, Vora SM, et al. Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature. 2021;593:607–11.

    Article  CAS  PubMed  Google Scholar 

  39. Miao R, Jiang C, Chang WY, Zhang H, An J, Ho F, et al. Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis. Immunity. 2023;56:2523–41.e2528.

    Article  CAS  PubMed  Google Scholar 

  40. Orzalli MH, Prochera A, Payne L, Smith A, Garlick JA, Kagan JC. Virus-mediated inactivation of anti-apoptotic Bcl-2 family members promotes Gasdermin-E-dependent pyroptosis in barrier epithelial cells. Immunity. 2021;54:1447–62.e1445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Graham JM Isolation of nuclei and nuclear membranes from animal tissues. Curr Protoc Cell Biol. 2001;Chapter 3:3.10.11-13.10.19.

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Acknowledgements

We thank Yingyu Chen (Peking University) for technical help. This work was supported by the National Natural Science Foundation of China (92369104, 82271790, 92169113), the Beijing Natural Science Foundation (JQ23028, 7212067), the National Key R&D Program of China (2021YFA1300202, 2022YFC2302900), the Strategic Priority Research Programs of the Chinese Academy of Sciences (XDB29020000), the Key Research Program of Frontier Sciences of Chinese Academy of Sciences (ZDBS-LY-SM025), the CAS Project for Young Scientists in Basic Research (YSBR-010), the Fok Ying Tung Education Foundation to P.X., the Youth Innovation Promotion Association of CAS to S.W.

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Author notes

  1. These authors contributed equally: Qiannv Liu, Weitao Li.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China

    Qiannv Liu, Weitao Li, Yan Qian, Chunlei Wang, Chun Kong, Mengqian Li, Liangliang Sun, Lang Sun, Changtao Jiang & Pengyan Xia

  2. NHC Key Laboratory of Medical Immunology, Peking University, Beijing, 100191, China

    Qiannv Liu, Weitao Li, Yan Qian, Chunlei Wang, Chun Kong, Mengqian Li, Liangliang Sun, Lang Sun, Changtao Jiang & Pengyan Xia

  3. Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing, 100191, China

    Qiannv Liu, Weitao Li, Yan Qian, Chunlei Wang, Chun Kong, Mengqian Li, Liangliang Sun, Lang Sun & Pengyan Xia

  4. State Key Laboratory of Female Fertility Preservation, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China

    Yanli Pang

  5. National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China

    Yanli Pang

  6. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, 100191, China

    Changtao Jiang

  7. Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing, 100191, China

    Changtao Jiang

  8. CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China

    Shuo Wang

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  1. Qiannv Liu
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Contributions

Q.L. and W.L. performed the experiments and analyzed the data; Y.Q., C.W., C.K., M.L., LL.S. and L.S. performed the experiments; S.W., Y.P. and C.J. analyzed the data; P.X. initiated the study, designed and performed the experiments, analyzed the data, and wrote the paper.

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Correspondence to Shuo Wang or Pengyan Xia.

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Liu, Q., Li, W., Qian, Y. et al. The TET3 inflammasome senses unique long HSV-1 proteins for virus particle budding from the nucleus. Cell Mol Immunol 21, 1322–1334 (2024). https://doi.org/10.1038/s41423-024-01221-2

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