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Interferon alpha (IFNα)-induced TRIM22 interrupts HCV replication by ubiquitinating NS5A

Cellular & Molecular Immunology volume 13, pages 94–102 (2016)Cite this article

Abstract

TRIM22, a tripartite-motif (TRIM) protein, is upregulated upon interferon alpha (IFNα) administration to hepatitis C virus (HCV)-infected patients. However, the physiological role of TRIM22 upregulation remains unclear. Here, we describe a potential antiviral function of TRIM22's targeting of the HCV NS5A protein. NS5A is important for HCV replication and for resistance to IFNα therapy. During the first 24 h following the initiation of IFNα treatment, upregulation of TRIM22 in the peripheral blood mononuclear cells (PBMCs) of HCV patients correlated with a decrease in viral titer. This phenomenon was confirmed in the hepatocyte-derived cell line Huh-7, which is highly permissive for HCV infection. TRIM22 over-expression inhibited HCV replication, and Small interfering RNA (siRNA)-mediated knockdown of TRIM22 diminished IFNα-induced anti-HCV function. Furthermore, we determined that TRIM22 ubiquitinates NS5A in a concentration-dependent manner. In summary, our results suggest that TRIM22 upregulation is associated with HCV decline during IFNα treatment and plays an important role in controlling HCV replication in vitro.

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Acknowledgements

We thank R Bartenschlager for providing the CON1 replicon and T Wakita for providing the JFH1 virus. We thank Wanyin Tao, Qiang Ding, Yu Xiang and Yongfen Xu for experimental support. We thank Dahui Zhao, Shuai Yang and all of the other nurses who helped collect patient blood. We thank Shijie Sun and Jizheng He from Roche Diagnostics, China, for support with the COBAS technique. We thank Li Li and Wenjing Xuan for ordering and preparing the experimental reagents. This work was supported by a grant from the National 973 Key Project (2013CB530504), the National 863 Key Project (2012AA020103), National Science and Technology Major Projects (2013ZX10004-101-005, 2012ZX10002-007-003 and 2013ZX10004-003-003), grants from the National Natural Science Foundation of China (31030029, 31230024 and 81361120409) and by the CAS/SAFEA International Partnership Program for Creative Research Teams.

Author information

Author notes

  1. Chen Yang, Xinhao Zhao and Dakang Sun: These authors contributed equally to this work.

  2. Dr B Sun, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; New Biological Building, No. 320 Yueyang Road, Shanghai 200031, China. E-mail: bsun@sibs.ac.cn

  3. Dr JQ Niu, Hepatology Section, First Hospital, University of Jilin, No. 71 Xinmin Street, Changchun 130021, China. E-mail: junqiniu@aliyun.com

  4. Dr J Zhong, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China; New Biological Building, No. 320 Yueyang Road, Shanghai 200031, China. E-mail: jzhong@sibs.ac.cn

Authors and Affiliations

  1. State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Chen Yang & Bing Sun

  2. Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Xinhao Zhao, Leilei Yang, Chang Chong, Jin Zhong & Bing Sun

  3. Hepatology Section, First Hospital, University of Jilin, Changchun, China

    Yu Pan, Xiumei Chi, Yanhang Gao, Xiaodong Shi, Haibo Sun, Juan Lv, Yuanda Gao & Junqi Niu

  4. Infectious Diseases Department, Fourth Hospital, University of Jilin, Changchun, China

    Moli Wang

  5. Experiment Center of Clinical Medicine, Affiliated Hospital of Binzhou Medical University, Binzhou, China

    Dakang Sun

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Yang, C., Zhao, X., Sun, D. et al. Interferon alpha (IFNα)-induced TRIM22 interrupts HCV replication by ubiquitinating NS5A. Cell Mol Immunol 13, 94–102 (2016). https://doi.org/10.1038/cmi.2014.131

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