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Human TRIM14 protects transgenic mice from influenza A viral infection without activation of other innate immunity pathways

Abstract

TRIM14 is an important component of innate immunity that defends organism from various viruses. It was shown that TRIM14 restricted influenza A virus (IAV) infection in cell cultures in an interferon-independent manner. However, it remained unclear whether TRIM14 affects IAV reproduction and immune system responses upon IAV infection in vivo. In order to investigate the effects of TRIM14 at the organismal level we generated transgenic mice overexpressing human TRIM14 gene. We found that IAV reproduction was strongly inhibited in lungs of transgenic mice, resulting in the increased survival of transgenic animals. Strikingly, upon IAV infection, the transcription of genes encoding interferons, IL-6, IL-1β, and TNFα was notably weaker in lungs of transgenic animals than that in control mice, thus indicating the absence of significant induction of interferon and inflammatory responses. In spleen of transgenic mice, where TRIM14 was unexpectedly downregulated, upon IAV infection the transcription of genes encoding interferons was oppositely increased. Therefore, we demonstrated the key role of TRIM14 in anti-IAV protection in the model organism that is realized without noticeable activation of other innate immune system pathways.

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Fig. 1: The influence of TRIM14 on IAV infection in transgenic mice lines Tg1 and Tg4.
Fig. 2: TRIM14 transcription level is increased in lung and decreased in spleen of transgenic mice.
Fig. 3: IFN response is not induced in the lung of transgenic mice upon IAV infection.
Fig. 4: IFN response is enhanced in the spleen of transgenic mice after 24 h of IAV infection.
Fig. 5: Pro-inflammatory response is partially inhibited in the lung of transgenic mice upon IAV infection.
Fig. 6: A proposed model of the influence of TRIM14 overexpression on the immune gene transcription upon IAV infection.

References

  1. 1.

    Ozato K, Shin DM, Chang TH, Morse HC III. TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol. 2008;8:849–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Nisole S, Stoye JP, Saib A. TRIM family proteins: retroviral restriction and antiviral defense. Nat Rev Microbiol. 2005;3:799–808.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Hatakeyama S. TRIM proteins and cancer. Nat Rev Cancer. 2011;11:792–804.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Hatakeyama S. TRIM family proteins: roles in autophagy, immunity, and carcinogenesis. Trends Biochem Sci. 2017;42:297–311.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Nenasheva VV, Tarantul VZ. Many faces of TRIM proteins on the road from pluripotency to neurogenesis. Stem Cells Dev. 2020;29:1–14.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Versteeg GA, Benke S, García-Sastre A, Rajsbaum R. InTRIMsic immunity: positive and negative regulation of immune signaling by tripartite motif proteins. Cytokine Growth Factor Rev. 2014;25:563–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Khan R, Khan A, Ali A, Idrees M. The interplay between viruses and TRIM family proteins. Rev Med Virol. 2019;29:e2028.

    PubMed  Article  Google Scholar 

  8. 8.

    van Gent M, Sparrer KMJ, Gack MU. TRIM proteins and their roles in antiviral host defenses. Annu Rev Virol. 2018;5:385–405.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9.

    van Tol S, Hage A, Giraldo MI, Bharaj P, Rajsbaum R. The TRIMendous role of TRIMs in virus-host interactions. Vaccines (Basel). 2017;5:E23. pii

    Article  CAS  Google Scholar 

  10. 10.

    Di Pietro A, Kajaste-Rudnitski A, Oteiza A, Nicora L, Towers GJ, Mechti N, et al. TRIM22 inhibits influenza A virus infection by targeting the viral nucleoprotein for degradation. J Virol. 2013;87:4523–33.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Yang C, Zhao X, Sun D, Yang L, Chong C, Pan Y, et al. Interferon alpha (IFNα)-induced TRIM22 interrupts HCV replication by ubiquitinating NS5A. Cell Mol Immunol. 2015;13:94–102.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Fan W, Liu T, Li X, Zhou Y, Wu M, Cui X, et al. TRIM52: A nuclear TRIM protein that positively regulates the nuclear factor-kappa B signaling pathway. Mol Immunol. 2017;82:114–22.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Fu B, Wang L, Ding H, Schwamborn JC, Li S, Dorf ME. TRIM32 senses and restricts influenza A virus by ubiquitination of PB1 polymerase. PLoS Pathog. 2015;11:e1004960.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Patil G, Zhao M, Song K, Hao W, Bouchereau D, Wang L, et al. TRIM41-mediated ubiquitination of nucleoprotein limits influenza A virus infection. J Virol. 2018;92:e00905–18. pii

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Seo GJ, Kim C, Shin WJ, Sklan EH, Eoh H, Jung JU. TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing. Nat Commun. 2018;9:613.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. 16.

    Wu X, Wang J, Wang S, Wu F, Chen Z, Li C, et al. Inhibition of influenza A virus replication by TRIM14 via its multifaceted protein-protein interaction with NP. Front Microbiol. 2019;10:344.

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Sun N, Jiang L, Ye M, Wang Y, Wang G, Wan X, et al. TRIM35 mediates protection against influenza infection by activating TRAF3 and degrading viral PB2. Protein Cell. 2020;11:894–914.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    Tarantul VZ, Nikolaev AI, Martynenko A, Hannig H, Hunsmann G, Bodemer W. Differential gene expression in B-cell non-Hodgkin’s lymphoma of SIV-infected monkey. AIDS Res Hum Retroviruses. 2000;16:173–9.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Nenasheva VV, Nikolaev AI, Martynenko AV, Kaplanskaya IB, Bodemer W, Hunsmann G, et al. Differential gene expression in HIV/SIV-associated and spontaneous lymphomas. Int J Med Sci. 2005;2:122–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Wang S, Chen Y, Li C, Wu Y, Guo L, Peng C, et al. TRIM14 inhibits hepatitis C virus infection by SPRY domain-dependent targeted degradation of the viral NS5A protein. Sci Rep. 2016;6:32336.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Tan G, Xu F, Song H, Yuan Y, Xiao Q, Ma F, et al. Identification of TRIM14 as a type I IFN-stimulated gene controlling hepatitis B virus replication by targeting HBx. Front Immunol. 2018;9:1872.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Nenasheva VV, Kovaleva GV, Uryvaev LV, Ionova KS, Dedova AV, Vorkunova GK, et al. Enhanced expression of trim14 gene suppressed Sindbis virus reproduction and modulated the transcription of a large number of genes of innate immunity. Immunol Res. 2015;62:255–62.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Rajsbaum R, Stoye JP, O’Garra A. Type I interferon-dependent and -independent expression of tripartite motif proteins in immune cells. Eur J Immunol. 2008;38:619–30.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Carthagena L, Bergamaschi A, Luna JM, David A, Uchil PD, Margottin-Goguet F, et al. Human TRIM gene expression in response to interferons. PLoS One. 2009;4:e4894.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Uchil PD, Hinz A, Siegel S, Coenen-Stass A, Pertel T, Luban J, et al. TRIM protein-mediated regulation of inflammatory and innate immune signaling and its association with antiretroviral activity. J Virol. 2013;87:257–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Zhou Z, Jia X, Xue Q, Dou Z, Ma Y, Zhao Z, et al. TRIM14 is a mitochondrial adaptor that facilitates retinoic acid-inducible gene-I-like receptor-mediated innate immune response. Proc Natl Acad Sci USA. 2014;111:E245–54.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Nogales A, Aydillo T, Ávila-Pérez G, Escalera A, Chiem K, Cadagan R, et al. Functional characterization and direct comparison of influenza A, B, C, and D NS1 proteins in vitro and in vivo. Front Microbiol. 2019;10:2862.

    PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Fukuyama S, Kawaoka Y. The pathogenesis of influenza virus infections: the contributions of virus and host factors. Curr Opin Immunol. 2011;23:481–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    World Health Organization Influenza (seasonal). http://www.who.int/mediacentre/factsheets/fs211/en/ (2016). Accessed 28 April 2016.

  30. 30.

    Nuñez IA, Ross TM. A review of H5Nx avian influenza viruses. Ther Adv Vaccines Immunother. 2019;7:2515135518821625.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Yamaji R, Saad MD, Davis CT, Swayne DE, Wang D, Wong FYK, et al. Pandemic potential of highly pathogenic avian influenza clade 2.3.4.4 A(H5) viruses. Rev Med Virol. 2020;30:e2099.

    PubMed  Article  Google Scholar 

  32. 32.

    Shin DL, Hatesuer B, Bergmann S, Nedelko T, Schughart K. Protection from severe influenza virus infections in mice carrying the Mx1 influenza virus resistance gene strongly depends on genetic background. J Virol. 2015;89:9998–10009.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Kenney AD, McMichael TM, Imas A, Chesarino NM, Zhang L, Dorn LE, et al. IFITM3 protects the heart during influenza virus infection. Proc Natl Acad Sci USA. 2019;116:18607–12.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Smith AM, Adler FR, Ribeiro RM, Gutenkunst RN, McAuley JL, McCullers JA, et al. Kinetics of coinfection with influenza A virus and Streptococcus pneumoniae. PLoS Pathog. 2013;9:e1003238.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Levene RE, Gaglia MM. Host shutoff in influenza A virus: many means to an end. Viruses. 2018;10:E475. pii

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Chen M, Meng Q, Qin Y, Liang P, Tan P, He L, et al. TRIM14 inhibits cGAS degradation mediated by selective autophagy receptor p62 to promote innate immune responses. Mol Cell. 2016;64:105–19.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Gu Y, Hsu AC, Pang Z, Pan H, Zuo X, Wang G, et al. Role of the innate cytokine storm induced by the influenza A virus. Viral Immunol. 2019;32:244–51.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Davidson S, Maini MK, Wack A. Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J Interferon Cytokine Res. 2015;35:252–64.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Hoffpauir CT, Bell SL, West KO, Jing T, Wagner AR, Torres-Odio S, et al. TRIM14 is a key regulator of the type I IFN response during Mycobacterium tuberculosis infection. J Immunol. 2020;205:153–67.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Feng S, Cai X, Li Y, Jian X, Zhang L, Li B. Tripartite motif-containing 14 (TRIM14) promotes epithelial-mesenchymal transition via ZEB2 in glioblastoma cells. J Exp Clin Cancer Res. 2019;38:57.

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Hu G, Pen W, Wang M. TRIM14 promotes breast cancer cell proliferation by inhibiting apoptosis. Oncol Res. 2019;27:439–47.

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Jin Z, Li H, Hong X, Ying G, Lu X, Zhuang L, et al. TRIM14 promotes colorectal cancer cell migration and invasion through the SPHK1/STAT3 pathway. Cancer Cell Int. 2018;18:202.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Shen W, Jin Z, Tong X, Wang H, Zhuang L, Lu X, et al. TRIM14 promotes cell proliferation and inhibits apoptosis by suppressing PTEN in colorectal cancer. Cancer Manag Res. 2019;11:5725–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Sun W, Wang Y, Li D, Wu Y, Ji Q, Sun T. Tripartite motif containing 14: an oncogene in papillary thyroid carcinoma. Biochem Biophys Res Commun. 2020;521:360–7.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Tarantul VZ. Many faces of TRIM family proteins on the field of oncoimmunology. Univers J Oncol. 2018;1:1–37. http://uapublications.com/oncology/pdf/UJO-v1-1002.pdf http://uapublications.com/oncology/pdf/UJO-v1-1002.pdf

    Google Scholar 

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Acknowledgements

This work was supported by the Russian Foundation for Basic Research (grant numbers 18–04–00733, 18–34–00484, and 20–015–00272) and Russian Fundamental Scientific Research Program (АААА-А19-119022290059-8).

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Correspondence to Valentina V. Nenasheva.

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Nenasheva, V.V., Nikitenko, N.A., Stepanenko, E.A. et al. Human TRIM14 protects transgenic mice from influenza A viral infection without activation of other innate immunity pathways. Genes Immun 22, 56–63 (2021). https://doi.org/10.1038/s41435-021-00128-6

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