Citation: Bo Wang, Leike Zhang, Fei Deng, Zhihong Hu, Manli Wang, Jia Liu. Hsp90 β is critical for the infection of severe fever with thrombocytopenia syndrome virus .VIROLOGICA SINICA, 2024, 39(1) : 113-122.  http://dx.doi.org/10.1016/j.virs.2023.11.008

Hsp90 β is critical for the infection of severe fever with thrombocytopenia syndrome virus

  • Corresponding author: Jia Liu, liujia@wh.iov.cn
  • Received Date: 21 February 2023
    Accepted Date: 22 November 2023
    Available online: 24 November 2023
  • Severe fever with thrombocytopenia syndrome (SFTS) caused by the SFTS virus (SFTSV) is an emerging disease in East Asia with a fatality rate of up to 30%. However, the viral-host interaction of SFTSV remains largely unknown. The heat-shock protein 90 (Hsp90) family consists of highly conserved chaperones that fold and remodel proteins and has a broad impact on the infection of many viruses. Here, we showed that Hsp90 is an important host factor involved in SFTSV infection. Hsp90 inhibitors significantly reduced SFTSV replication, viral protein expression, and the formation of inclusion bodies consisting of nonstructural proteins (NSs). Among viral proteins, NSs appeared to be the most reduced when Hsp90 inhibitors were used, and further analysis showed that their translation was affected. Co-immunoprecipitation of NSs with four isomers of Hsp90 showed that Hsp90 β specifically interacted with them. Knockdown of Hsp90 β expression also inhibited replication of SFTSV. These results suggest that Hsp90 β plays a critical role during SFTSV infection and could be a potential target for the development of drugs against SFTS.

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    1. Abudurexiti, A., Adkins, S., Alioto, D., Alkhovsky, S.V., Avšič-Županc, T., Ballinger, M.J., Bente, D.A., Beer, M., Bergeron, É., Blair, C.D., Briese, T., Buchmeier, M.J., Burt, F.J., Calisher, C.H., Cháng, C., Charrel, R.N., Choi, I.R., Clegg, J.C.S., De La Torre, J.C., De Lamballerie, X., Dèng, F., Di Serio, F., Digiaro, M., Drebot, M.A., Duàn, X., Ebihara, H., Elbeaino, T., Ergünay, K., Fulhorst, C.F., Garrison, A.R., Gāo, G.F., Gonzalez, J.J., Groschup, M.H., Günther, S., Haenni, A.L., Hall, R.A., Hepojoki, J., Hewson, R., Hú, Z., Hughes, H.R., Jonson, M.G., Junglen, S., Klempa, B., Klingström, J., Kòu, C., Laenen, L., Lambert, A.J., Langevin, S.A., Liu, D., Lukashevich, I.S., Luò, T., Lǚ, C., Maes, P., De Souza, W.M., Marklewitz, M., Martelli, G.P., Matsuno, K., Mielke-Ehret, N., Minutolo, M., Mirazimi, A., Moming, A., Mühlbach, H.P., Naidu, R., Navarro, B., Nunes, M.R.T., Palacios, G., Papa, A., Pauvolid-Corrêa, A., Pawęska, J.T., Qiáo, J., Radoshitzky, S.R., Resende, R.O., Romanowski, V., Sall, A.A., Salvato, M.S., Sasaya, T., Shěn, S., Shí, X., Shirako, Y., Simmonds, P., Sironi, M., Song, J.W., Spengler, J.R., Stenglein, M.D., Sū, Z., Sūn, S., Táng, S., Turina, M., Wáng, B., Wáng, C., Wáng, H., Wáng, J., Wèi, T., Whitfield, A.E., Zerbini, F.M., Zhāng, J., Zhāng, L., Zhāng, Y., Zhang, Y.Z., Zhāng, Y., Zhou, X., Zhū, L.,Kuhn, J.H., 2019. Taxonomy of the order Bunyavirales: update 2019. Arch Virol, 164, 1949-1965.

    2. Albornoz, A., Hoffmann, A.B., Lozach, P.Y.,Tischler, N.D., 2016. Early Bunyavirus-Host Cell Interactions. Viruses, 8.

    3. Basta, S., Stoessel, R., Basler, M., Van Den Broek, M.,Groettrup, M., 2005. Cross-presentation of the long-lived lymphocytic chori-omeningitis virus nucleoprotein does not require neosynthesis and is enhanced via heat shock proteins. J Immunol, 175, 796-805.

    4. Burch, A.D.,Weller, S.K., 2005. Herpes simplex virus type 1 DNA polymerase requires the mammalian chaperone hsp90 for proper localization to the nucleus. J Virol, 79, 10740-10749.

    5. Chen, B., Piel, W.H., Gui, L., Bruford, E.,Monteiro, A., 2005. The HSP90 family of genes in the human genome: insights into their divergence and evolution. Genomics, 86, 627-637.

    6. Chen, W., Sin, S.H., Wen, K.W., Damania, B.,Dittmer, D.P., 2012. Hsp90 inhibitors are efficacious against Kaposi Sarcoma by en-hancing the degradation of the essential viral gene LANA, of the viral co-receptor EphA2 as well as other client proteins. PLoS Pathog, 8, e1003048.

    7. Choi, Y., Park, S.J., Sun, Y., Yoo, J.S., Pudupakam, R.S., Foo, S.S., Shin, W.J., Chen, S.B., Tsichlis, P.N., Lee, W.J., Lee, J.S., Li, W., Brennan, B., Choi, Y.K.,Jung, J.U., 2019. Severe fever with thrombocytopenia syndrome phlebovirus non-structural protein activates TPL2 signalling pathway for viral immunopathogenesis. Nat Microbiol, 4, 429-437.

    8. Gao, L.,Harhaj, E.W., 2013. HSP90 protects the human T-cell leukemia virus type 1 (HTLV-1) tax oncoprotein from proteasomal degradation to support NF-kappaB activation and HTLV-1 replication. J Virol, 87, 13640-13654.

    9. Gu, X.L., Su, W.Q., Zhou, C.M., Fang, L.Z., Zhu, K., Ma, D.Q., Jiang, F.C., Li, Z.M., Li, D., Duan, S.H., Peng, Q.M., Wang, R., Jiang, Y., Han, H.J.,Yu, X.J., 2022. SFTSV infection in rodents and their ectoparasitic chiggers. PLoS Negl Trop Dis, 16, e0010698.

    10. Hong, Y., Bai, M., Qi, X., Li, C., Liang, M., Li, D., Cardona, C.J.,Xing, Z., 2019. Suppression of the IFN-α and -β Induction through Sequestering IRF7 into Viral Inclusion Bodies by Nonstructural Protein NSs in Severe Fever with Thrombocytopenia Syn-drome Bunyavirus Infection. J Immunol, 202, 841-856.

    11. Hoter, A., El-Sabban, M.E.,Naim, H.Y., 2018. The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease. Int J Mol Sci, 19.

    12. Khalil, J., Kato, H.,Fujita, T., 2021. The Role of Non-Structural Protein NSs in the Pathogenesis of Severe Fever with Thrombocytopenia Syndrome. Viruses, 13.

    13. Kitagawa, Y., Sakai, M., Shimojima, M., Saijo, M., Itoh, M.,Gotoh, B., 2018. Nonstructural protein of severe fever with thrombocy-topenia syndrome phlebovirus targets STAT2 and not STAT1 to inhibit type I interferon-stimulated JAK-STAT signaling. Microbes Infect, 20, 360-368.

    14. Kramer, G., Boehringer, D., Ban, N.,Bukau, B., 2009. The ribosome as a platform for co-translational processing, folding and targeting of newly synthesized proteins. Nat Struct Mol Biol, 16, 589-597.

    15. Lam, T.T., Liu, W., Bowden, T.A., Cui, N., Zhuang, L., Liu, K., Zhang, Y.Y., Cao, W.C.,Pybus, O.G., 2013. Evolutionary and molec-ular analysis of the emergent severe fever with thrombocytopenia syndrome virus. Epidemics, 5, 1-10.

    16. Liu, Y., Li, Q., Hu, W., Wu, J., Wang, Y., Mei, L., Walker, D.H., Ren, J., Wang, Y.,Yu, X.J., 2012. Person-to-person transmission of severe fever with thrombocytopenia syndrome virus. Vector Borne Zoonotic Dis, 12, 156-160.

    17. Min, Y.Q., Ning, Y.J., Wang, H.,Deng, F., 2020. A RIG-I-like receptor directs antiviral responses to a bunyavirus and is antagonized by virus-induced blockade of TRIM25-mediated ubiquitination. J Biol Chem, 295, 9691-9711.

    18. Naito, T., Momose, F., Kawaguchi, A.,Nagata, K., 2007. Involvement of Hsp90 in assembly and nuclear import of influenza virus RNA polymerase subunits. J Virol, 81, 1339-1349.

    19. Ning, Y.J., Feng, K., Min, Y.Q., Cao, W.C., Wang, M., Deng, F., Hu, Z.,Wang, H., 2015. Disruption of type I interferon signaling by the nonstructural protein of severe fever with thrombocytopenia syndrome virus via the hijacking of STAT2 and STAT1 into inclusion bodies. J Virol, 89, 4227-4236.

    20. Qu, B., Qi, X., Wu, X., Liang, M., Li, C., Cardona, C.J., Xu, W., Tang, F., Li, Z., Wu, B., Powell, K., Wegner, M., Li, D.,Xing, Z., 2012. Suppression of the interferon and NF-kappaB responses by severe fever with thrombocytopenia syndrome virus. J Virol, 86, 8388-8401.

    21. Reyes-Del Valle, J., Chávez-Salinas, S., Medina, F.,Del Angel, R.M., 2005. Heat shock protein 90 and heat shock protein 70 are com-ponents of dengue virus receptor complex in human cells. J Virol, 79, 4557-4567.

    22. Rochlin, I., Benach, J.L., Furie, M.B., Thanassi, D.G.,Kim, H.K., 2022. Rapid invasion and expansion of the Asian longhorned tick (Haemaphysalis longicornis) into a new area on Long Island, New York, USA. Ticks Tick Borne Dis, 14, 102088.

    23. Solit, D.B.,Chiosis, G., 2008. Development and application of Hsp90 inhibitors. Drug Discov Today, 13, 38-43.

    24. Song, P., Zheng, N., Liu, Y., Tian, C., Wu, X., Ma, X., Chen, D., Zou, X., Wang, G., Wang, H., Zhang, Y., Lu, S., Wu, C.,Wu, Z., 2018. Deficient humoral responses and disrupted B-cell immunity are associated with fatal SFTSV infection. Nat Commun, 9, 3328.

    25. Sun, Q., Qi, X., Zhang, Y., Wu, X., Liang, M., Li, C., Li, D., Cardona, C.J.,Xing, Z., 2016. Synaptogyrin-2 Promotes Replication of a Novel Tick-borne Bunyavirus through Interacting with Viral Nonstructural Protein NSs. J Biol Chem, 291, 16138-16149.

    26. Sun, X., Barlow, E.A., Ma, S., Hagemeier, S.R., Duellman, S.J., Burgess, R.R., Tellam, J., Khanna, R.,Kenney, S.C., 2010. Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism. Proc Natl Acad Sci U S A, 107, 3146-3151.

    27. Sun, X., Bristol, J.A., Iwahori, S., Hagemeier, S.R., Meng, Q., Barlow, E.A., Fingeroth, J.D., Tarakanova, V.L., Kalejta, R.F.,Kenney, S.C., 2013. Hsp90 inhibitor 17-DMAG decreases expression of conserved herpesvirus protein kinases and reduces virus production in Epstein-Barr virus-infected cells. J Virol, 87, 10126-10138.

    28. Tsou, Y.L., Lin, Y.W., Chang, H.W., Lin, H.Y., Shao, H.Y., Yu, S.L., Liu, C.C., Chitra, E., Sia, C.,Chow, Y.H., 2013. Heat shock protein 90: role in enterovirus 71 entry and assembly and potential target for therapy. PLoS One, 8, e77133.

    29. Tufts, D.M., Goodman, L.B., Benedict, M.C., Davis, A.D., Vanacker, M.C.,Diuk-Wasser, M., 2021. Association of the invasive Haemaphysalis longicornis tick with vertebrate hosts, other native tick vectors, and tick-borne pathogens in New York City, USA. Int J Parasitol, 51, 149-157.

    30. Wang, Y., Jin, F., Wang, R., Li, F., Wu, Y., Kitazato, K.,Wang, Y., 2017. HSP90: a promising broad-spectrum antiviral drug target. Arch Virol, 162, 3269-3282.

    31. Wu, X., Qi, X., Liang, M., Li, C., Cardona, C.J., Li, D.,Xing, Z., 2014a. Roles of viroplasm-like structures formed by nonstructural protein NSs in infection with severe fever with thrombocytopenia syndrome virus. Faseb j, 28, 2504-2516.

    32. Wu, X., Qi, X., Qu, B., Zhang, Z., Liang, M., Li, C., Cardona, C.J., Li, D.,Xing, Z., 2014b. Evasion of antiviral immunity through sequestering of TBK1/IKKε/IRF3 into viral inclusion bodies. J Virol, 88, 3067-3076.

    33. Yang, K., Shi, H., Qi, R., Sun, S., Tang, Y., Zhang, B.,Wang, C., 2006. Hsp90 regulates activation of interferon regulatory factor 3 and TBK-1 stabilization in Sendai virus-infected cells. Mol Biol Cell, 17, 1461-1471.

    34. Yoshikawa, R., Sakabe, S., Urata, S.,Yasuda, J., 2019. Species-Specific Pathogenicity of Severe Fever with Thrombocytopenia Syn-drome Virus Is Determined by Anti-STAT2 Activity of NSs. J Virol, 93.

    35. Yu, X.J., Liang, M.F., Zhang, S.Y., Liu, Y., Li, J.D., Sun, Y.L., Zhang, L., Zhang, Q.F., Popov, V.L., Li, C., Qu, J., Li, Q., Zhang, Y.P., Hai, R., Wu, W., Wang, Q., Zhan, F.X., Wang, X.J., Kan, B., Wang, S.W., Wan, K.L., Jing, H.Q., Lu, J.X., Yin, W.W., Zhou, H., Guan, X.H., Liu, J.F., Bi, Z.Q., Liu, G.H., Ren, J., Wang, H., Zhao, Z., Song, J.D., He, J.R., Wan, T., Zhang, J.S., Fu, X.P., Sun, L.N., Dong, X.P., Feng, Z.J., Yang, W.Z., Hong, T., Zhang, Y., Walker, D.H., Wang, Y.,Li, D.X., 2011. Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med, 364, 1523-1532.

    36. Zhang, J., Li, H., Liu, Y., Zhao, K., Wei, S., Sugarman, E.T., Liu, L.,Zhang, G., 2022. Targeting HSP90 as a Novel Therapy for Cancer: Mechanistic Insights and Translational Relevance. Cells, 11.

    37. Zhang, L.K., Wang, B., Xin, Q., Shang, W., Shen, S., Xiao, G., Deng, F., Wang, H., Hu, Z.,Wang, M., 2019. Quantitative Proteomic Analysis Reveals Unfolded-Protein Response Involved in Severe Fever with Thrombocytopenia Syndrome Virus Infection. J Virol, 93.

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    Hsp90 β is critical for the infection of severe fever with thrombocytopenia syndrome virus

      Corresponding author: Jia Liu, liujia@wh.iov.cn
    • a. State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China;
    • b. The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, China

    Abstract: Severe fever with thrombocytopenia syndrome (SFTS) caused by the SFTS virus (SFTSV) is an emerging disease in East Asia with a fatality rate of up to 30%. However, the viral-host interaction of SFTSV remains largely unknown. The heat-shock protein 90 (Hsp90) family consists of highly conserved chaperones that fold and remodel proteins and has a broad impact on the infection of many viruses. Here, we showed that Hsp90 is an important host factor involved in SFTSV infection. Hsp90 inhibitors significantly reduced SFTSV replication, viral protein expression, and the formation of inclusion bodies consisting of nonstructural proteins (NSs). Among viral proteins, NSs appeared to be the most reduced when Hsp90 inhibitors were used, and further analysis showed that their translation was affected. Co-immunoprecipitation of NSs with four isomers of Hsp90 showed that Hsp90 β specifically interacted with them. Knockdown of Hsp90 β expression also inhibited replication of SFTSV. These results suggest that Hsp90 β plays a critical role during SFTSV infection and could be a potential target for the development of drugs against SFTS.

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