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Volume 40 Issue 2
April 2025
    Citation: Chen Li, Meng Zhou, Kaitao Zhao, Wenbo Liu, Chengliang Zhu, Xiaoming Cheng, Yuchen Xia. Sphingomyelin phosphodiesterase 3 as a novel host factor inhibiting hepatitis B virus transcription .VIROLOGICA SINICA, 2025, 40(2) : 292-295.  http://dx.doi.org/10.1016/j.virs.2025.02.004
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    Sphingomyelin phosphodiesterase 3 as a novel host factor inhibiting hepatitis B virus transcription

    • a. State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, 430072, China;

    • b. College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, China;

    • c. Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China;

    • d. Department of Pathology, Center for Pathology and Molecular Diagnostics, Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, TaiKang Medical School, Wuhan University, Wuhan, 430072, China;

    • e. Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China;

    • f. Hubei Jiangxia Laboratory, Wuhan, 430071, China;

    • g. Pingyuan Laboratory, Henan, 453001, China

    • Highlights
      1. SMPD3 is identified as a novel host factor that inhibits Hepatitis B virus (HBV) replication at the transcriptional level.
      2. SMPD3 knockdown enhances HBV replication in various cell models, increasing levels of HBsAg, HBeAg, and HBV DNA.
      3. Mechanistic studies reveal SMPD3's inhibition of HBV transcription without affecting RNA stability or promoter activity.
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    • Electronic Supplementary Material

      10.1016j.virs.2025.02.004-ESM.docx

      1. Easterbrook, P., Luhmann, N., Newman, M., Walsh, N., Lesi, O., Doherty, M., 2021. New WHO guidance for country validation of viral hepatitis B and C elimination. Lancet Gastroenterol. Hepatology 6, 778-780.

      2. Kim, W. J., Okimoto, R. A., Purton, L. E., Goodwin, M., Haserlat, S. M., Dayyani, F., Sweetser, D. A., McClatchey, A. I., Bernard, O. A., Look, A. T. et al., 2008. Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood 111, 4716-4722.

      3. Matsuzaka, Y., Tanihata, J., Ooshima, Y., Yamada, D., Sekiguchi, M., Miyatake, S., Aoki, Y., Terumitsu, M., Yashiro, R., Komaki, H. et al., 2020. The nSMase2/Smpd3 gene modulates the severity of muscular dystrophy and the emotional stress response in mdx mice. BMC Med. 18, 343.

      4. Revill, K., Wang, T., Lachenmayer, A., Kojima, K., Harrington, A., Li, J., Hoshida, Y., Llovet, J. M., Powers, S., 2013. Genome-wide methylation analysis and epigenetic unmasking identify tumor suppressor genes in hepatocellular carcinoma. Gastroenterology 145, 1424-1435.

      5. Soudani, N., Hage-Sleiman, R., Karam, W., Dbaibo, G., Zaraket, H., 2019. Ceramide suppresses influenza A virus replication in vitro. J. Virol. 93, e00053.-19.

      6. Stoffel, W., Hammels, I., Jenke, B., Binczek, E., Schmidt-Soltau, I., Brodesser, S., Schauss, A., Etich, J., Heilig, J., Zaucke, F., 2016. Neutral sphingomyelinase (SMPD3) deficiency disrupts the Golgi secretory pathway and causes growth inhibition. Cell Death Dis. 7, e2488.

      7. Teng, Y., Xu, Z., Zhao, K., Zhong, Y., Wang, J., Zhao, L., Zheng, Z., Hou, W., Zhu, C., Chen, X. et al., 2021. Novel function of SART1 in HNF4α transcriptional regulation contributes to its antiviral role during HBV infection. J. Hepatol. 75, 1072-1082.

      8. Voisset, C., Lavie, M., Helle, F., Op, De Beeck A, Bilheu, A., Bertrand-Michel, J., Terce, F., Cocquerel, L., Wychowski, C., Vu-Dac, N. et al., 2008. Ceramide enrichment of the plasma membrane induces CD81 internalization and inhibits hepatitis C virus entry. Cell. Microbiol. 10, 606-617.

      9. Wang, S., Chen, S., Sun, J., Han, P., Xu, B., Li, X., Zhong, Y., Xu, Z., Zhang, P., Mi, P. et al., 2023. m6A modification-tuned sphingolipid metabolism regulates postnatal liver development in male mice. Nat. Metab. 5, 842-860.

      10. Xia, Y., Liang, T., 2019. Development of direct-acting antiviral and host-targeting agents for treatment of hepatitis B virus infection. Gastroenterology 156, 311-324.

      11. Xia, Y., Guo, H., 2020. Hepatitis B virus cccDNA: formation, regulation and therapeutic potential. Antivir. Res. 180, 104824.

      12. Xia, Y., Cheng, X., Nilsson, T., Zhang, M., Zhao, G., Inuzuka, T., Teng, Y., Li, Y., Anderson, D. E., Holdorf, M. et al., 2023. Nucleolin binds to and regulates transcription of hepatitis B virus covalently closed circular DNA minichromosome. Proc. Natl. Acad. Sci. U. S. A. 120, e2306390120.

      13. Zhao, K., Liu, A., Xia, Y.,2020. Insights into hepatitis B virus DNA integration-55 years after virus discovery. Innovation (Camb.) 1, 100034.

      14. Zhao, K., Wang, J., Wang, Z., Wang, M., Li, C., Xu, Z., Zhan, Q., Guo, F., Cheng, X., Xia, Y., 2025. Hepatitis B virus hijacks MRE11-RAD50-NBS1 complex to form its minichromosome. PLoS Pathog. 21, e1012824.

      15. Zhou, W., Woodson, M., Sherman, M. B., Neelakanta, G., Sultana, H., 2019. Exosomes mediate Zika virus transmission through SMPD3 neutral sphingomyelinase in cortical neurons. Emerg. Microb. Infect. 8, 307-326.

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      Sphingomyelin phosphodiesterase 3 as a novel host factor inhibiting hepatitis B virus transcription

        Corresponding author: Xiaoming Cheng, xiaoming.cheng@whu.edu.cn
        Corresponding author: Yuchen Xia, yuchenxia@whu.edu.cn
      • a. State Key Laboratory of Virology and Biosafety, Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, 430072, China;
      • b. College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, China;
      • c. Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, 430060, China;
      • d. Department of Pathology, Center for Pathology and Molecular Diagnostics, Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, TaiKang Medical School, Wuhan University, Wuhan, 430072, China;
      • e. Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan, 430071, China;
      • f. Hubei Jiangxia Laboratory, Wuhan, 430071, China;
      • g. Pingyuan Laboratory, Henan, 453001, China
      • Received Date: 09 November 2024
      • Accepted Date: 23 February 2025

      Abstract: Highlights
      1. SMPD3 is identified as a novel host factor that inhibits Hepatitis B virus (HBV) replication at the transcriptional level.
      2. SMPD3 knockdown enhances HBV replication in various cell models, increasing levels of HBsAg, HBeAg, and HBV DNA.
      3. Mechanistic studies reveal SMPD3's inhibition of HBV transcription without affecting RNA stability or promoter activity.

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