Front Immunol. 2018 Aug 13;9:1872. doi: 10.3389/fimmu.2018.01872. eCollection 2018.
Identification of TRIM14 as a Type I IFN-Stimulated Gene Controlling Hepatitis B Virus Replication by Targeting HBx.
Tan G1, Xu F1, Song H1, Yuan Y2, Xiao Q3, Ma F4, Qin FX4, Cheng G1,4,5.
Author information
1
Department of Immunology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, China.
2
Department of Medicine Laboratory, The First Hospital of Jilin University, Changchun, China.
3
Department of Nephrology, The First Hospital, Jilin University, Changchun, China.
4
Suzhou Institute of Systems Medicine, Suzhou, China.
5
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA, United States.
Abstract
Hepatitis B virus (HBV) remains a major cause of hepatic disease that threatens human health worldwide. Type I IFN (IFN-I) therapy is an important therapeutic option for HBV patients. The antiviral effect of IFN is mainly mediated via upregulation of the expressions of the downstream IFN-stimulated genes. However, the mechanisms by which IFN induces ISG production and inhibits HBV replication are yet to be clarified. TRIM14 was recently reported as a key molecule in the IFN-signaling pathway that regulates IFN production in response to viral infection. In this study, we sought to understand the mechanisms by which IFN restricts HBV replication. We confirmed that TRIM14 is an ISG in the hepatic cells, and that the pattern-recognition receptor ligands polyI:C and polydAdT induce TRIM14 dependent on IFN-I production. In addition, IFN-I-activated STAT1 (but not STAT3) directly bound to the TRIM14 promoter and mediated the induction of TRIM14. Interestingly, TRIM14 played an important role in IFN-I-mediated inhibition of HBV, and the TRIM14 SPRY domain interacted with the C-terminal of HBx, which might block the role of HBx in facilitating HBV replication by inhibiting the formation of the Smc-HBx-DDB1 complex. Thus, our study clearly demonstrates that TRIM14 is a STAT1-dependent ISG, and that the IFN-I-TRIM14-HBx axis shows an alternative way to understand the mechanism by which IFN-I inhibits virus replication.
KEYWORDS:
STAT1; TRIM14; hepatitis B virus X protein; hepatitis B virus replication; type I IFN