Citation: Yang Xiao, Shuofeng Yuan, Ye Qiu, Xing-Yi Ge. Virome-wide analysis of histone modification mimicry motifs carried by viral proteins .VIROLOGICA SINICA, 2024, 39(5) : 793-801.  http://dx.doi.org/10.1016/j.virs.2024.09.004

Virome-wide analysis of histone modification mimicry motifs carried by viral proteins

cstr: 32224.14.j.virs.2024.09.004
  • Corresponding author: Ye Qiu, qiuye@hnu.edu.cn
    Xing-Yi Ge, xyge@hnu.edu.cn
  • Received Date: 16 April 2023
    Accepted Date: 11 September 2024
    Available online: 16 September 2024
  • Histone mimicry (HM) refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins. These motifs have the potential to interfere with host cell epigenome and counteract antiviral response. Recent research shows that HM is critical for the pathogenesis and transmissibility of influenza virus and coronavirus. However, the distribution, characteristics, and functions of HM in eukaryotic viruses remain obscure. Herein, we developed a bioinformatic pipeline, Histone Motif Scan (HiScan), to identify HM motifs in viral proteins and predict their functions in silico. By analyzing 592,643 viral proteins using HiScan, we found that putative HM motifs were widely distributed in most viral proteins. Among animal viruses, the ratio of HM motifs between DNA viruses and RNA viruses was approximately 1.9:1, and viruses with smaller genomes had a higher density of HM motifs. Notably, coronaviruses exhibited an uneven distribution of HM motifs, with betacoronaviruses (including most human pathogenic coronaviruses) harboring more HM motifs than other coronaviruses, primarily in the NSP3, S, and N proteins. In summary, our virome-wide screening of HM motifs using HiScan revealed extensive but uneven distribution of HM motifs in most viral proteins, with a preference in DNA viruses. Viral HM may play an important role in modulating viral pathogenicity and virus-host interactions, making it an attractive area of research in virology and antiviral medication.

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    1. Avgousti, D.C., Della Fera, A.N., Otter, C.J., Herrmann, C., Pancholi, N.J., Weitzman, M.D., 2017. Adenovirus core protein VII downregulates the DNA damage response on the host genome. J. Virol. 91, e01089-17.

    2. Avgousti, D.C., Herrmann, C., Kulej, K., Pancholi, N.J., Sekulic, N., Petrescu, J., Molden, R.C., Blumenthal, D., Paris, A.J., Reyes, E.D., et al., 2016. A core viral protein binds host nucleosomes to sequester immune danger signals. Nature 535, 173-177.

    3. Baisya, D.R., Lonardi, S., 2021. Prediction of histone post-translational modifications using deep learning. Bioinformatics 36, 5610-5617.

    4. Benveniste, D., Sonntag, H. J., Sanguinetti, G., Sproul, D., 2014. Transcription factor binding predicts histone modifications in human cell lines. Proc. Natl. Acad. Sci. U.S.A. 111, 13367-13372.

    5. Brownell, J.E., Zhou, J., Ranalli, T., Kobayashi, R., Edmondson, D.G., Roth, S.Y., Allis, C.D., 1996. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84, 843-851.

    6. Bryson, T.D., De Ioannes, P., Valencia-Sanchez, M.I., Henikoff, J.G., Talbert, P.B., Lee, R., La Scola, B., Armache, K.J., Henikoff, S., 2022. A giant virus genome is densely packaged by stable nucleosomes within virions. Mol. Cell 82, 4458-4470.e5.

    7. Challberg, M.D., Kelly, T.J., 1989. Animal virus DNA replication. Annu. Rev. Biochem. 58, 671-717.

    8. Champagne, J., Mordente, K., Nagel, R., Agami, R., 2022. Slippy-Sloppy translation: a tale of programmed and induced-ribosomal frameshifting. Trends Genet. 38, 1123-1133.

    9. Cheng, K., Xu, Y., Yang, C., Ouellette, L., Niu, L., Zhou, X., Chu, L., Zhuang, F., Liu, J., Wu, H., et al., 2020. Histone tales: lysine methylation, a protagonist in Arabidopsis development. J. Exp. Bot. 71, 793-807.

    10. Cheung, P., Tanner, K.G., Cheung, W.L., Sassone-Corsi, P., Denu, J.M., Allis, C.D., 2000. Synergistic coupling of histone H3 phosphorylation and acetylation in response to epidermal growth factor stimulation. Mol. Cell 5, 905-915.

    11. Cui, J., Li, F., Shi, Z.L., 2019. Origin and evolution of pathogenic coronaviruses. Nat. Rev. Microbiol. 17, 181-192.

    12. Elde, N.C., Malik, H.S., 2009. The evolutionary conundrum of pathogen mimicry. Nat. Rev. Microbiol. 7, 787-797.

    13. Hans, F., Dimitrov, S., 2001. Histone H3 phosphorylation and cell division. Oncogene 20, 3021-3027.

    14. Jackson, J.P., Johnson, L., Jasencakova, Z., Zhang, X., PerezBurgos, L., Singh, P.B., Cheng, X., Schubert, I., Jenuwein, T., Jacobsen, S.E., 2004. Dimethylation of histone H3 lysine 9 is a critical mark for DNA methylation and gene silencing in Arabidopsis thaliana. Chromosoma 112, 308-315.

    15. Jacob, Y., Michaels, S.D., 2009. H3K27me1 is E(z) in animals, but not in plants. Epigenetics 4, 366-369.

    16. Jenuwein, T., Allis, C.D., 2001. Translating the histone code. Science 293, 1074-1080.

    17. Kasinath, V., Beck, C., Sauer, P., Poepsel, S., Kosmatka, J., Faini, M., Toso, D., Aebersold, R., Nogales, E., 2021. JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications. Science 371, eabc3393.

    18. Kee, J., Thudium, S., Renner, D.M., Glastad, K., Palozola, K., Zhang, Z., Li, Y., Lan, Y., Cesare, J., Poleshko, A., et al., 2022. SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry. Nature 610, 381-388.

    19. Lafon-Hughes, L., 2023. Towards understanding long COVID: SARS-CoV-2 strikes the host cell nucleus. Pathogens 12, 806.

    20. Lee, D.Y., Teyssier, C., Strahl, B.D., Stallcup, M.R., 2005. Role of protein methylation in regulation of transcription. Endocr. Rev. 26, 147-170.

    21. Liu, P., Wang, X., Sun, Y., Zhao, H., Cheng, F., Wang, J., Yang, F., Hu, J., Zhang, H., Wang, C.-C., et al., 2022. SARS-CoV-2 ORF8 reshapes the ER through forming mixed disulfides with ER oxidoreductases. Redox Biol. 54, 102388.

    22. Louten, J., 2016. Virus Replication. Essential Human Virology. Elsevier Inc., pp. 49-70.

    23. Marazzi, I., Ho, J.S.Y., Kim, J., Manicassamy, B., Dewell, S., Albrecht, R.A., Seibert, C.W., Schaefer, U., Jeffrey, K.L., Prinjha, R.K., et al., 2012. Suppression of the antiviral response by an influenza histone mimic. Nature 483, 428-433.

    24. Mattiroli, F., Penengo, L., 2021. Histone ubiquitination: an integrative signaling platform in genome stability. Trends Genet. 37, 566-581.

    25. Merx, J., Hintzen, J.C.J., Proietti, G., Elferink, H., Wang, Y., Porzberg, M.R.B., Sondag, D., Bilgin, N., Park, J., Mecinovic, J., et al., 2022. Investigation of in vitro histone H3 glycosylation using H3 tail peptides. Sci. Rep. 12, 19251.

    26. Moustaqil, M., Ollivier, E., Chiu, H.-P., Van Tol, S., Rudolffi-Soto, P., Stevens, C., Bhumkar, A., Hunter, D.J.B., Freiberg, A.N., Jacques, D., et al., 2021. SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species. Emerg. Microb. Infect. 10, 178-195.

    27. Nowak, S.J., Corces, V.G., 2004. Phosphorylation of histone H3: a balancing act between chromosome condensation and transcriptional activation. Trends Genet. 20, 214-220.

    28. Pellett, P.E., Mitra, S., Holland, T.C., 2014. Basics of virology. Handb. Clin. Neurol. 123, 45-66.

    29. Peterson, C.L., Laniel, M.A., 2004. Histones and histone modifications. Curr. Biol. 14, R546-R551.

    30. Ryu, H.-Y., Zhao, D., Li, J., Su, D., Hochstrasser, M., 2020. Histone sumoylation promotes Set3 histone-deacetylase complex-mediated transcriptional regulation. Nucleic Acids Res. 48, 12151-12168.

    31. Sampath, Srihari C., Marazzi, I., Yap, K.L., Sampath, Srinath C., Krutchinsky, A.N., Mecklenbrauker, I., Viale, A., Rudensky, E., Zhou, M.-M., Chait, B.T., et al., 2007. Methylation of a histone mimic within the histone methyltransferase G9a regulates protein complex assembly. Mol. Cell 27, 596-608.

    32. Schaefer, U., Ho, J.S.Y., Prinjha, R.K., Tarakhovsky, A., 2013. The “histone mimicry” by pathogens. Cold Spring Harbor Symp. Quant. Biol. 78, 81-90.

    33. Shvedunova, M., Akhtar, A., 2022. Modulation of cellular processes by histone and non-histone protein acetylation. Nat. Rev. Mol. Cell Biol. 23, 329-349.

    34. Summers, W.C., 2009. Virus Infection. Encyclopedia of Microbiology, third ed. Elsevier Inc., pp.546.

    35. Suzuki, K., Juelich, T., Lim, H., Ishida, T., Watanebe, T., Cooper, D.A., Rao, S., Kelleher, A.D., 2008. Closed chromatin architecture is induced by an RNA duplex targeting the HIV-1 promoter region. J. Biol. Chem. 283, 23353-23363.

    36. Tamburri, S., Lavarone, E., Fernandez-Perez, D., Conway, E., Zanotti, M., Manganaro, D., Pasini, D., 2020. Histone H2AK119 mono-ubiquitination is essential for polycomb-mediated transcriptional repression. Mol. Cell 77, 840-856.e5.

    37. Tarakhovsky, A., Prinjha, R.K., 2018. Drawing on disorder: how viruses use histone mimicry to their advantage. J. Exp. Med. 215, 1777-1787.

    38. Worden, E.J., Hoffmann, N.A., Hicks, C.W., Wolberger, C., 2019. Mechanism of cross-talk between H2B ubiquitination and H3 methylation by Dot1L. Cell 176, 1490-1501.e12.

    39. Yang, H., Rao, Z., 2021. Structural biology of SARS-CoV-2 and implications for therapeutic development. Nat. Rev. Microbiol. 19, 685-700.

    40. Yin, Q., Wu, M., Liu, Q., Lv, H., Jiang, R., 2019. DeepHistone: a deep learning approach to predicting histone modifications. BMC Genom. 20, 193.

    41. Yoon, S., Kim, M., Lee, H., Kang, G., Bedi, K., Margulies, K.B., Jain, R., Nam, K.-I., Kook, H., Eom, G.H., 2021. S-nitrosylation of histone deacetylase 2 by neuronal nitric oxide synthase as a mechanism of diastolic dysfunction. Circulation 143, 1912-1925.

    42. Yu, Y., Wen, H., Shi, X., 2021. Histone mimics: more tales to read. Biochem. J. 478, 2789-2791.

    43. Yuan, S., Gao, X., Tang, K., Cai, J.P., Hu, M., Luo, P., Wen, L., Ye, Z.W., Luo, C., Tsang, J.O. et al., 2022. Targeting papain-like protease for broad-spectrum coronavirus inhibition. Protein Cell. 13, 940-953.

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    Virome-wide analysis of histone modification mimicry motifs carried by viral proteins

      Corresponding author: Ye Qiu, qiuye@hnu.edu.cn
      Corresponding author: Xing-Yi Ge, xyge@hnu.edu.cn
    • a. Hunan Provincial Key Laboratory of Medical Virology, Institute of Pathogen Biology and Immunology, College of Biology, Hunan University, Changsha, 410012, China;
    • b. Department of Microbiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, 999077, China

    Abstract: Histone mimicry (HM) refers to the presence of short linear motifs in viral proteins that mimic critical regions of host histone proteins. These motifs have the potential to interfere with host cell epigenome and counteract antiviral response. Recent research shows that HM is critical for the pathogenesis and transmissibility of influenza virus and coronavirus. However, the distribution, characteristics, and functions of HM in eukaryotic viruses remain obscure. Herein, we developed a bioinformatic pipeline, Histone Motif Scan (HiScan), to identify HM motifs in viral proteins and predict their functions in silico. By analyzing 592,643 viral proteins using HiScan, we found that putative HM motifs were widely distributed in most viral proteins. Among animal viruses, the ratio of HM motifs between DNA viruses and RNA viruses was approximately 1.9:1, and viruses with smaller genomes had a higher density of HM motifs. Notably, coronaviruses exhibited an uneven distribution of HM motifs, with betacoronaviruses (including most human pathogenic coronaviruses) harboring more HM motifs than other coronaviruses, primarily in the NSP3, S, and N proteins. In summary, our virome-wide screening of HM motifs using HiScan revealed extensive but uneven distribution of HM motifs in most viral proteins, with a preference in DNA viruses. Viral HM may play an important role in modulating viral pathogenicity and virus-host interactions, making it an attractive area of research in virology and antiviral medication.

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