FoxO4 inhibits HBV core promoter activity through ERK-mediated downregulation of HNF4α
FoxO4 inhibits HBV core promoter activity through ERK-mediated downregulation of HNF4α
复制标题
FoxO4 通过 ERK 介导的 HNF4α 下调抑制 HBV 核心启动子活性。
DOI：
10.1016/j.antiviral.2019.104568
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发表时间：
2019-10-01
影响因子：
7.6
通讯作者：
Gao, Bo
中科院分区：
文献类型：
--
作者：
Li, Lijie;Li, Yuqi;Gao, Bo
乙肝病毒感染仍然是一个全球性的健康问题，每年造成近100万人死亡。叉头盒O(Forkhead box O，FoxO)转录因子在调节多种生理过程中发挥重要作用。最近的研究表明，FOXO参与了抗病毒反应。在目前的研究中，我们发现，乙肝病毒诱导的FOXO4蛋白表达显著下调，而对FOXO1和FOX03的表达影响不大。进一步的研究表明，FOXO4在体外和体内都对乙肝病毒的转录和复制有抑制作用。从机制上讲，FOXO4通过靶向乙肝病毒核心启动子发挥抗乙肝病毒的作用。此外，FOXO4通过下调肝细胞核因子-4α(HNF4α)抑制HBVC启动子活性，而ERK信号是FOXO4抑制HNF4α和HBVC启动子活性所必需的。综上所述，FOXO4通过激活ERK途径抑制HNF4α的表达而显示抗HBV活性，靶向FOXO4可能成为一种新的抗乙肝病毒感染的治疗策略。
Hepatitis B virus (HBV) infection remains a global health problem, causing nearly one million deaths annually. Forkhead box O (FoxO) transcription factors play important roles in modulating diverse physiological processes. Recent studies show that FoxOs are involved in antiviral responses. In present investigation, we found that HBV induced significant down-regulation of FoxO4 protein, while had little effect on the expression of FoxO1 and FoxO3. Further study showed that FoxO4 displayed inhibitory effect on HBV transcription and replication both in vitro and in vivo. Mechanistically, it was found that FoxO4 exerted its anti-HBV activity by targeting HBV core promoter. Further, FoxO4 was revealed to inhibit HBV core promoter activity via downregulating hepatocyte nuclear factor-4 alpha (HNF4 alpha), and ERK signaling was required for FoxO4-mediated suppression of HNF4 alpha and HBV core promoter activity. Together, these data indicated that FoxO4 displayed anti-HBV activity by suppressing HNF4 alpha expression via activation of ERK pathway, and targeting FoxO4 might present as a novel therapeutic strategy against HBV infection.