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Type I IFN augments IL-27-dependent TRIM25 expression to inhibit HBV replication

Cellular & Molecular Immunology volume 15, pages 272–281 (2018)Cite this article

Abstract

Hepatitis B virus (HBV) can cause chronic hepatitis B, which may lead to cirrhosis and liver cancer. Type I interferon (IFN) is an approved drug for the treatment of chronic hepatitis B. However, the fundamental mechanisms of antiviral action by type I IFN and the downstream signaling pathway are unclear. TRIM25 is an IFN-stimulated gene (ISG) that has an important role in RIG-I ubiquitination and activation. Whether TRIM25 is induced in liver cells by type I IFN to mediate anti-HBV function remains unclear. Here we report that interleukin-27 (IL-27) has a critical role in IFN-induced TRIM25 upregulation. TRIM25 induction requires both STAT1 and STAT3. In TRIM25 knockout HepG2 cells, type I IFN production was consistently attenuated and HBV replication was increased, whereas overexpression of TRIM25 in HepG2 cells resulted in elevated IFN production and reduced HBV replication. More interestingly, we found that TRIM25 expression was downregulated in HBV patients and the addition of serum samples from HBV patients could inhibit TRIM25 expression in HepG2 cells, suggesting that HBV might have involved a mechanism to inhibit antiviral ISG expression and induce IFN resistance. Collectively, our results demonstrate that type I IFN -induced TRIM25 is an important factor in inhibiting HBV replication, and the IFN-IL-27-TRIM25 axis may represent a new target for treating HBV infection.

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Acknowledgements

This work was supported in part by the National Natural Science Foundation, China, Jilin Provincial Science and Technology Department of the Youth Fund Project, and Jilin University Bethune training program (grant no. 81401290, 20160520161JH, 470110000456 to GT). CAMS Initiative for Innovative Medicine (no. CAMS-I2M) to FXQ and GC.

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Author notes

  1. Guangyun Tan and Qingfei Xiao: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, Institute of Translational Medicine, The First Hospital, Jilin University, Changchun, 130061, Jilin, PR China

    Guangyun Tan, Hongxiao Song, Fengchao Xu, Xiaosong Wang, F Xiao-Feng Qin & Genhong Cheng

  2. Department of Nephrology, The First Hospital of Jilin University, Changchun, 130021, Jilin, PR China

    Qingfei Xiao

  3. Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, PR China

    Feng Ma, Di Peng, F Xiao-Feng Qin & Genhong Cheng

  4. Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China

    Feng Ma, Di Peng, F Xiao-Feng Qin & Genhong Cheng

  5. Department of Obstetrics, The First Hospital, Jilin University, Changchun, 130021, Jilin, PR China

    Na Li

  6. Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021, Jilin, PR China

    Junqi Niu & Pujun Gao

  7. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, 90095, CA, USA

    Genhong Cheng

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  1. Guangyun Tan
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Corresponding authors

Correspondence to Pujun Gao, F Xiao-Feng Qin or Genhong Cheng.

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Tan, G., Xiao, Q., Song, H. et al. Type I IFN augments IL-27-dependent TRIM25 expression to inhibit HBV replication. Cell Mol Immunol 15, 272–281 (2018). https://doi.org/10.1038/cmi.2016.67

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