Type I IFN augments IL-27-dependent TRIM25 expression to inhibit HBV replication
Type I IFN augments IL-27-dependent TRIM25 expression to inhibit HBV replication
复制标题
I 型 IFN 增强 IL-27 依赖性 TRIM25 表达以抑制 HBV 复制
DOI：
10.1038/cmi.2016.67
复制
发表时间：
2018-03-01
影响因子：
24.1
通讯作者：
Cheng, Genhong
中科院分区：
文献类型：
--
作者：
Tan, Guangyun;Xiao, Qingfei;Cheng, Genhong
B型肝炎病毒（HBV）可引起慢性B型肝炎，可能导致肝硬化和肝癌。I型干扰素（IFN）是一种获批用于治疗慢性乙型肝炎（chronic hepatitis B）的药物。然而，I型IFN的抗病毒作用的基本机制和下游信号通路尚不清楚。TRIM 25是一种干扰素刺激的基因（ISG），在RIG-I泛素化和激活中起重要作用。TRIM 25是否在肝细胞中被I型IFN诱导以介导抗HBV功能尚不清楚。在这里，我们报告，白细胞介素-27（IL-27）在IFN诱导的TRIM 25上调中起着关键作用。TRIM 25的诱导需要STAT 1和STAT 3。在TRIM 25敲除的HepG 2细胞中，I型IFN的产生持续减弱，HBV复制增加，而在HepG 2细胞中TRIM 25的过表达导致IFN的产生升高，HBV复制减少。更有趣的是，我们发现TRIM 25在HBV患者中表达下调，并且加入HBV患者血清样品可以抑制HepG 2细胞中TRIM 25的表达，这表明HBV可能参与了抑制抗病毒ISG表达并诱导IFN抗性的机制。总的来说，我们的研究结果表明，I型IFN诱导的TRIM 25是抑制HBV复制的重要因素，IFN-IL-27-TRIM 25轴可能代表治疗HBV感染的新靶点。
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.