Citation: Lishi Liu, Zhen Chen, Kui Zhang, Haojie Hao, Li Ma, Haizhou Liu, Baocheng Yu, Shuang Ding, Xueyan Zhang, Miao Zhu, Xiang Guo, Yi Liu, Haibin Liu, Fang Huang, Ke Peng, Wuxiang Guan. NSUN2 mediates distinct pathways to regulate enterovirus 71 replication .VIROLOGICA SINICA, 2024, 39(4) : 574-586.  http://dx.doi.org/10.1016/j.virs.2024.05.002

NSUN2 mediates distinct pathways to regulate enterovirus 71 replication

cstr: 32224.14.j.virs.2024.05.002
  • Increasing evidences suggest that the methyltransferase NSUN2 catalyzes 5-methylcytosine (m5C) modifications on viral RNAs, which are essential for the replication of various viruses. Despite the function of m5C deposition is well characterized, other potential roles of NSUN2 in regulating viral replication remain largely unknown. In this study, the m5C modified residues catalyzed by NSUN2 on enterovirus 71 (EV71) RNAs were mapped. NSUN2, along with m5C modifications, played multiple roles during the EV71 life cycle. Functional m5C modified nucleotides increased the translational efficiency and stability of EV71 RNAs. Additionally, NSUN2 was found to target the viral protein VP1 for binding and promote its stability by inhibiting the ubiquitination. Furthermore, both viral replication and pathogenicity in mice were largely attenuated when functional m5C residues were mutated. Taken together, this study characterizes distinct pathways mediated by NSUN2 in regulating EV71 replication, and highlights the importance of its catalyzed m5C modifications on EV71 RNAs for the viral replication and pathogenicity.

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    1. Arango, D., Sturgill, D., Alhusaini, N., Dillman, A.A., Sweet, T.J., Hanson, G., Hosogane, M., Sinclair, W.R., Nanan, K.K., Mandler, M.D., Fox, S.D., Zengeya, T.T., Andresson, T., Meier, J.L., Coller, J., Oberdoerffer, S., 2018. Acetylation of cytidine in mRNA promotes translation efficiency. Cell. 175, 1872-1886 e1824.

    2. Bohnsack, K.E., Hobartner, C., Bohnsack, M.T., 2019. Eukaryotic 5-methylcytosine (m(5)C) RNA methyltransferases: mechanisms, cellular functions, and links to disease. Genes. 10, 102.

    3. Cardosa, M.J., Perera, D., Brown, B.A., Cheon, D., Chan, H.M., Chan, K.P., Cho, H., McMinn, P., 2003. Molecular epidemiology of human enterovirus 71 strains and recent outbreaks in the Asia-Pacific region: comparative analysis of the VP1 and VP4 genes. Emerg. Infect. Dis. 9, 461-468.

    4. Chen, B., Sumi, A., Toyoda, S., Hu, Q., Zhou, D., Mise, K., Zhao, J., Kobayashi, N., 2015. Time series analysis of reported cases of hand, foot, and mouth disease from 2010 to 2013 in Wuhan, China. BMC Infect. Dis. 15, 495.

    5. Chen, X., Li, A., Sun, B.F., Yang, Y., Han, Y.N., Yuan, X., Chen, R.X., Wei, W.S., Liu, Y., Gao, C.C., Chen, Y.S., Zhang, M., Ma, X.D., Liu, Z.W., Luo, J.H., Lyu, C., Wang, H.L., Ma, J., Zhao, Y.L., Zhou, F.J., Huang, Y., Xie, D., Yang, Y.G., 2019. 5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs. Nat. Cell Biol. 21, 978-990.

    6. Chen, Y., Yang, W., Zhao, Y., Yang, Y., 2021. Dynamic transcriptomic m(5) C and its regulatory role in RNA processing. Wiley Interdiscip Rev RNA. 12, e1639.

    7. Courtney, D.G., Kennedy, E.M., Dumm, R.E., Bogerd, H.P., Tsai, K., Heaton, N.S., Cullen, B.R., 2017. Epitranscriptomic enhancement of influenza A virus gene expression and replication. Cell Host Microbe. 22, 377-386 e375.

    8. Courtney, D.G., Chalem, A., Bogerd, H.P., Law, B.A., Kennedy, E.M., Holley, C.L., Cullen, B.R., 2019a. Extensive epitranscriptomic methylation of A and C residues on murine leukemia virus transcripts enhances viral gene expression. mBio. 10, e01209-19.

    9. Courtney, D.G., Tsai, K., Bogerd, H.P., Kennedy, E.M., Law, B.A., Emery, A., Swanstrom, R., Holley, C.L., Cullen, B.R., 2019b. Epitranscriptomic addition of m(5)C to HIV-1 transcripts regulates viral gene expression. Cell Host Microbe. 26, 217-227 e216.

    10. Dawson, M.A., Kouzarides, T., 2012. Cancer epigenetics: from mechanism to therapy. Cell. 150, 12-27.

    11. Deng, L., Kumar, J., Rose, R., McIntyre, W., Fabris, D., 2022. Analyzing RNA posttranscriptional modifications to decipher the epitranscriptomic code. Mass Spectrom. Rev. e21798.

    12. Ding, S., Liu, H., Liu, L., Ma, L., Chen, Z., Zhu, M., Liu, L., Zhang, X., Hao, H., Zuo, L., Yang, J., Wu, X., Zhou, P., Huang, F., Zhu, F., Guan, W., 2024. Epigenetic addition of m5C to HBV transcripts promotes viral replication and evasion of innate antiviral responses. Cell Death Dis. 15, 39.

    13. Eckwahl, M., Xu, R., Michalkiewicz, J., Zhang, W., Patel, P., Cai, Z., Pan, T., 2020. 5-Methylcytosine RNA modifications promote retrovirus replication in an ALYREF reader protein-dependent manner. J. Virol. 94, e00544-20.

    14. Feng, J., Xu, T., He, M., Li, J., Yao, P., Ma, C., Yang, S., Xu, Z., Yan, K., Chen, X., Wang, H., Liu, J., Zeng, C., Xia, Y., Yan, H., Zhou, L., Chen, Y., 2023. NSUN2-mediated m5C modification of HBV RNA positively regulates HBV replication. PLoS Pathog. 19, e1011808.

    15. Feng, M., Xie, X., Han, G., Zhang, T., Li, Y., Li, Y., Yin, R., Wang, Q., Zhang, T., Wang, P., Hu, J., Cheng, Y., Gao, Z., Wang, J., Chang, J., Cui, M., Gao, K., Chai, J., Liu, W., Guo, C., Li, S., Liu, L., Zhou, F., Chen, J., Zhang, H., 2021. YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner. Blood. 138, 71-85.

    16. Gao, Y., Fang, J., 2021. RNA 5-methylcytosine modification and its emerging role as an epitranscriptomic mark. RNA Biol. 18, 117-127.

    17. Hao, H., Hao, S., Chen, H., Chen, Z., Zhang, Y., Wang, J., Wang, H., Zhang, B., Qiu, J., Deng, F., Guan, W., 2019. N6-methyladenosine modification and METTL3 modulate enterovirus 71 replication. Nucleic Acids Res. 47, 362-374.

    18. Hao, H., Liu, W., Miao, Y., Ma, L., Yu, B., Liu, L., Yang, C., Zhang, K., Chen, Z., Yang, J., Zheng, Z., Zhang, B., Deng, F., Gong, P., Yuan, J., Hu, Z., Guan, W., 2022. N4-acetylcytidine regulates the replication and pathogenicity of enterovirus 71. Nucleic Acids Res. 50, 9339-9354.

    19. Hao, S., Zhang, J., Chen, Z., Xu, H., Wang, H., Guan, W., 2017. Alternative polyadenylation of human bocavirus at its 3' end is regulated by multiple elements and affects capsid expression. J. Virol. 91, e02026-16.

    20. Huang, F., Feng, Y., Peterlin, B.M., Fujinaga, K., 2022. P-TEFb is degraded by Siah1/2 in quiescent cells. Nucleic Acids Res. 50, 5000-5013.

    21. Hussain, S., Sajini, A.A., Blanco, S., Dietmann, S., Lombard, P., Sugimoto, Y., Paramor, M., Gleeson, J.G., Odom, D.T., Ule, J., Frye, M., 2013. NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs. Cell Rep. 4, 255-261.

    22. Imam, H., Kim, G.W., Siddiqui, A., 2020. Epitranscriptomic(N6-methyladenosine) modification of viral RNA and virus-host interactions. Front. Cell. Infect. Microbiol. 10, 584283.

    23. Kennedy, E.M., Bogerd, H.P., Kornepati, A.V., Kang, D., Ghoshal, D., Marshall, J.B., Poling, B.C., Tsai, K., Gokhale, N.S., Horner, S.M., Cullen, B.R., 2016. Posttranscriptional m(6)A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe. 19, 675-685.

    24. Kim, D., Lee, J.Y., Yang, J.S., Kim, J.W., Kim, V.N., Chang, H., 2020. The architecture of SARS-CoV-2 transcriptome. Cell. 181, 914-921 e910.

    25. Li, N., Hui, H., Bray, B., Gonzalez, G.M., Zeller, M., Anderson, K.G., Knight, R., Smith, D., Wang, Y., Carlin, A.F., Rana, T.M., 2021. METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection. Cell Rep. 35, 109091.

    26. Lichinchi, G., Gao, S., Saletore, Y., Gonzalez, G.M., Bansal, V., Wang, Y., Mason, C.E., Rana, T.M., 2016. Dynamics of the human and viral m(6)A RNA methylomes during HIV-1 infection of T cells. Nat Microbiol. 1, 16011.

    27. Lin, J.Y., Li, M.L., Huang, P.N., Chien, K.Y., Horng, J.T., Shih, S.R., 2008. Heterogeneous nuclear ribonuclear protein K interacts with the enterovirus 71 5' untranslated region and participates in virus replication. J. Gen. Virol. 89, 2540-2549.

    28. Liu, Y., Zheng, Z., Shu, B., Meng, J., Zhang, Y., Zheng, C., Ke, X., Gong, P., Hu, Q., Wang, H., 2016. SUMO modification stabilizes enterovirus 71 polymerase 3D to facilitate viral replication. J. Virol. 90, 10472-10485.

    29. Lopata, A., Kniss, A., Lohr, F., Rogov, V.V., Dotsch, V., 2020. Ubiquitination in the ERAD process. Int. J. Mol. Sci. 21, 5369.

    30. Lv, X., Liu, X., Zhao, M., Wu, H., Zhang, W., Lu, Q., Chen, X., 2021. RNA methylation in systemic lupus erythematosus. Front. Cell Dev. Biol. 9, 696559.

    31. Majumder, K., Morales, A.J., 2021. Utilization of host cell chromosome conformation by viral pathogens: knowing when to hold and when to fold. Front. Immunol. 12, 633762.

    32. Meyer, K.D., 2019. m(6)A-mediated translation regulation. Biochim Biophys Acta Gene Regul Mech. 1862, 301-309.

    33. Motorin, Y., Helm, M., 2011. RNA nucleotide methylation. Wiley Interdiscip Rev RNA. 2, 611-631.

    34. Pathinayake, P.S., Hsu, A.C., Wark, P.A., 2015. Innate immunity and immune evasion by enterovirus 71. Viruses. 7, 6613-6630.

    35. Reid, R., Greene, P.J., Santi, D.V., 1999. Exposition of a family of RNA m(5)C methyltransferases from searching genomic and proteomic sequences. Nucleic Acids Res. 27, 3138-3145.

    36. Roundtree, I.A., Evans, M.E., Pan, T., He, C., 2017. Dynamic RNA modifications in gene expression regulation. Cell. 169, 1187-1200.

    37. Schumann, U., Zhang, H.N., Sibbritt, T., Pan, A., Horvath, A., Gross, S., Clark, S.J., Yang, L., Preiss, T., 2020. Multiple links between 5-methylcytosine content of mRNA and translation. BMC Biol. 18, 40.

    38. Shi, H., Wei, J., He, C., 2019. Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell. 74, 640-650.

    39. Song, P., Tayier, S., Cai, Z., Jia, G., 2021. RNA methylation in mammalian development and cancer. Cell Biol. Toxicol. 37, 811-831.

    40. Srinivas, K.P., Depledge, D.P., Abebe, J.S., Rice, S.A., Mohr, I., Wilson, A.C., 2021. Widespread remodeling of the m(6)A RNA-modification landscape by a viral regulator of RNA processing and export. Proc Natl Acad Sci U S A. 118, e2104805118.

    41. Sweeney, T.R., Abaeva, I.S., Pestova, T.V., Hellen, C.U., 2014. The mechanism of translation initiation on Type 1 picornavirus IRESs. EMBO J. 33, 76-92.

    42. Tsai, K., Jaguva Vasudevan, A.A., Martinez Campos, C., Emery, A., Swanstrom, R., Cullen, B.R., 2020. Acetylation of cytidine residues boosts HIV-1 gene expression by increasing viral RNA stability. Cell Host Microbe. 28, 306-312.e306.

    43. Wang, T., Kong, S., Tao, M., Ju, S., 2020. The potential role of RNA N6-methyladenosine in Cancer progression. Mol. Cancer. 19, 88.

    44. Wiener, D., Schwartz, S., 2021. The epitranscriptome beyond m(6)A. Nat. Rev. Genet. 22, 119-131.

    45. Wu, L., Candille, S.I., Choi, Y., Xie, D., Jiang, L., Li-Pook-Than, J., Tang, H., Snyder, M., 2013. Variation and genetic control of protein abundance in humans. Nature. 499, 79-82.

    46. Xiao, X., Qi, J., Lei, X., Wang, J., 2019. Interactions between enteroviruses and the inflammasome: new insights into viral pathogenesis. Front. Microbiol. 10, 321.

    47. Yang, X., Yang, Y., Sun, B.F., Chen, Y.S., Xu, J.W., Lai, W.Y., Li, A., Wang, X., Bhattarai, D.P., Xiao, W., Sun, H.Y., Zhu, Q., Ma, H.L., Adhikari, S., Sun, M., Hao, Y.J., Zhang, B., Huang, C.M., Huang, N., Jiang, G.B., Zhao, Y.L., Wang, H.L., Sun, Y.P., Yang, Y.G., 2017. 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m(5)C reader. Cell Res. 27, 606-625.

    48. Yang, Y., Wang, L., Han, X., Yang, W.L., Zhang, M., Ma, H.L., Sun, B.F., Li, A., Xia, J., Chen, J., Heng, J., Wu, B., Chen, Y.S., Xu, J.W., Yang, X., Yao, H., Sun, J., Lyu, C., Wang, H.L., Huang, Y., Sun, Y.P., Zhao, Y.L., Meng, A., Ma, J., Liu, F., Yang, Y.G., 2019. RNA 5-methylcytosine facilitates the maternal-to-zygotic transition by preventing maternal mRNA decay. Mol Cell. 75, 1188-1202.e1111.

    49. Zhang, X., Hao, H., Ma, L., Zhang, Y., Hu, X., Chen, Z., Liu, D., Yuan, J., Hu, Z., Guan, W., 2021. Methyltransferase-like 3 modulates severe acute respiratory syndrome coronavirus-2 RNA N6-methyladenosine modification and replication. mBio. 12, e0106721.

    50. Zhao, Y., Shi, Y., Shen, H., Xie, W., 2020. m(6)A-binding proteins: the emerging crucial performers in epigenetics. J. Hematol. Oncol. 13, 35.

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    NSUN2 mediates distinct pathways to regulate enterovirus 71 replication

      Corresponding author: Fang Huang, huangf@wh.iov.cn
      Corresponding author: Ke Peng, pengke@wh.iov.cn
      Corresponding author: Wuxiang Guan, guanwx@wh.iov.cn
    • a. Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China;
    • b. University of Chinese Academy of Sciences, Beijing, 100049, China;
    • c. Hubei Jiangxia Laboratory, Wuhan, Hubei, 430200, China

    Abstract: Increasing evidences suggest that the methyltransferase NSUN2 catalyzes 5-methylcytosine (m5C) modifications on viral RNAs, which are essential for the replication of various viruses. Despite the function of m5C deposition is well characterized, other potential roles of NSUN2 in regulating viral replication remain largely unknown. In this study, the m5C modified residues catalyzed by NSUN2 on enterovirus 71 (EV71) RNAs were mapped. NSUN2, along with m5C modifications, played multiple roles during the EV71 life cycle. Functional m5C modified nucleotides increased the translational efficiency and stability of EV71 RNAs. Additionally, NSUN2 was found to target the viral protein VP1 for binding and promote its stability by inhibiting the ubiquitination. Furthermore, both viral replication and pathogenicity in mice were largely attenuated when functional m5C residues were mutated. Taken together, this study characterizes distinct pathways mediated by NSUN2 in regulating EV71 replication, and highlights the importance of its catalyzed m5C modifications on EV71 RNAs for the viral replication and pathogenicity.

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