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SAMD4 family members suppress human hepatitis B virus by directly binding to the Smaug recognition region of viral RNA

Cellular & Molecular Immunology volume 18, pages 1032–1044 (2021)Cite this article

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Abstract

HBV infection initiates hepatitis B and promotes liver cirrhosis and hepatocellular carcinoma. IFN-α is commonly used in hepatitis B therapy, but how it inhibits HBV is not fully understood. We screened 285 human interferon-stimulated genes (ISGs) for anti-HBV activity using a cell-based assay, which revealed several anti-HBV ISGs. Among these ISGs, SAMD4A was the strongest suppressor of HBV replication. We found the binding site of SAMD4A in HBV RNA, which was a previously unidentified Smaug recognition region (SRE) sequence conserved in HBV variants. SAMD4A binds to the SRE site in viral RNA to trigger its degradation. The SAM domain in SAMD4A is critical for RNA binding and the C-terminal domain of SAMD4A is required for SAMD4A anti-HBV function. Human SAMD4B is a homolog of human SAMD4A but is not an ISG, and the murine genome encodes SAMD4. All these SAMD4 proteins suppressed HBV replication when overexpressed in vitro and in vivo. We also showed that knocking out the Samd4 gene in hepatocytes led to a higher level of HBV replication in mice and AAV-delivered SAMD4A expression reduced the virus titer in HBV-producing transgenic mice. In addition, a database analysis revealed a negative correlation between the levels of SAMD4A/B and HBV in patients. Our data suggest that SAMD4A is an important anti-HBV ISG for use in IFN therapy of hepatitis B and that the levels of SAMD4A/B expression are related to HBV sensitivity in humans.

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Acknowledgements

This work was supported by the National Scientific and Technological Major Project (2017ZX10202203-003), the National Natural Science Foundation of China (81788101, 31420103910, and 81630042), the 111 Project (B12001), and the National Science Foundation of China for Fostering Talents in Basic Research (J1310027).

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  1. These authors contributed equally: Yuze Wang, Xinrui Fan, Yunlong Song

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China

    Yuze Wang, Xinrui Fan, Yunlong Song, Yifei Liu, Ruixin Liu, Jianfeng Wu, Guo Fu & Jiahuai Han

  2. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, 361005, China

    Xiaoling Li, Quan Yuan & Ningshao Xia

  3. Cancer Research Center of Xiamen University, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, 361102, China

    Jiahuai Han

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Contributions

Y.W., X.F., Q.Y., N.X., and J.H. conceived and designed the experiments. Y.W., X.F., Y.S., R.L., Y.L., J.W., and X.L. performed the experiments. Y.W., X.F., Y.S., G.F., N.X., and J.H. analyzed the data. Y.W., X.F., and J.H. wrote the paper.

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Correspondence to Jiahuai Han.

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Wang, Y., Fan, X., Song, Y. et al. SAMD4 family members suppress human hepatitis B virus by directly binding to the Smaug recognition region of viral RNA. Cell Mol Immunol 18, 1032–1044 (2021). https://doi.org/10.1038/s41423-020-0431-x

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