通过靶向HBx鉴定TRIM14作为I型IFN刺激的基因控制乙型肝炎病毒

StephenW

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

PMID:
    30150992
PMCID:
    PMC6100580
DOI:
    10.3389/fimmu.2018.01872

StephenW

前免疫。 2018年8月13日; 9：1872年。 doi：10.3389 / fimmu.2018.01872。 eCollection 2018。
通过靶向HBx鉴定TRIM14作为I型IFN刺激的基因控制乙型肝炎病毒复制。
Tan G1，Xu F1，Song H1，Yuan Y2，Xiao Q3，Ma F4，Qin FX4，Cheng G1,4,5。
作者信息

1
    吉林大学第一医院转化医学研究所免疫学系，长春
2
    吉林大学第一医院医学实验室，长春
3
    吉林大学第一医院肾内科，长春
4
    苏州医学院，苏州，中国。
五
    美国加利福尼亚大学洛杉矶分校微生物学，免疫学和分子遗传学系。

抽象

乙型肝炎病毒（HBV）仍然是导致全球人类健康的肝病的主要原因。 I型IFN（IFN-I）疗法是HBV患者的重要治疗选择。 IFN的抗病毒作用主要通过上调下游IFN刺激基因的表达来介导。然而，IFN诱导ISG产生和抑制HBV复制的机制尚未阐明。最近报道TRIM14是IFN-信号传导途径中的关键分子，其调节响应于病毒感染的IFN产生。在本研究中，我们试图了解IFN限制HBV复制的机制。我们证实TRIM14是肝细胞中的ISG，并且模式识别受体配体polyI：C和polydAdT诱导TRIM14依赖于IFN-1产生。此外，IFN-1激活的STAT1（但不是STAT3）直接与TRIM14启动子结合并介导TRIM14的诱导。有趣的是，TRIM14在IFN-I介导的HBV抑制中起重要作用，并且TRIM14 SPRY结构域与HBx的C末端相互作用，这可能通过抑制Smc-的形成阻断HBx在促进HBV复制中的作用。 HBx-DDB1复合物。因此，我们的研究清楚地证明TRIM14是STAT1依赖性ISG，并且IFN-I-TRIM14-HBx轴显示了另一种方式来理解IFN-1抑制病毒复制的机制。
关键词：

STAT1; TRIM14;乙型肝炎病毒X蛋白;乙型肝炎病毒复制; I型IFN

结论：
    30150992
PMCID：
    PMC6100580
DOI：
    10.3389 / fimmu.2018.01872

StephenW

https://www.frontiersin.org/arti ... mmu.2018.01872/full