Hepatocyte nuclear factor 1α downregulates HBV gene expression and replication by activating the NF-κB signaling pathway.
Hepatocyte nuclear factor 1α downregulates HBV gene expression and replication by activating the NF-κB signaling pathway.
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DOI：
10.1371/journal.pone.0174017
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Xie Y
中科院分区：
文献类型：
--
作者：
Lin J;Gu C;Shen Z;Liu Y;Wang W;Tao S;Cui X;Liu J;Xie Y
肝细胞核因子1α（hepatocyte nuclear factor 1α，HNF 1 α）在调节B型肝炎病毒（hepatitis B virus，HBV）基因表达和复制中的作用尚不完全清楚。以往的研究报道HNF 1 α通过激活病毒Sp1启动子诱导病毒大表面蛋白（LHB）的表达。大量的LHB可阻断B型肝炎表面抗原（HBsAg）的分泌。我们发现HNF 1 α过表达抑制了Huh 7细胞中HBV基因的表达和复制，导致HBsAg、B e抗原（HBeAg）和病毒粒子产生显著减少。相反，内源性HNF 1 α表达的敲低增强了病毒基因的表达和复制。这种HNF 1 α介导的抑制作用不依赖于LHB。相反，HNF 1 α促进NF-κB p65的表达并减缓p65蛋白降解，导致p65在核中积聚并激活NF-κB信号传导，从而抑制HBV基因表达和复制。NF-κB信号通路的抑制剂IκBα-SR可消除HNF 1 α介导的这种抑制作用。虽然HNF 1 α的二聚化结构域是诱导LHBs表达所必需的，但HNF 1 α的所有结构域都是抑制HBV基因表达所必需的。我们的研究结果确定了HNF 1 α在HBV基因表达和复制调控中的新作用。
The role of hepatocyte nuclear factor 1α (HNF1α) in the regulation of gene expression and replication of hepatitis B virus (HBV) is not fully understood. Previous reports have documented the induction of the expression of viral large surface protein (LHBs) by HNF1α through activating viral Sp1 promoter. Large amount of LHBs can block the secretion of hepatitis B surface antigen (HBsAg). Here we found that HNF1α overexpression inhibited HBV gene expression and replication in Huh7 cells, resulting in marked decreases in HBsAg, hepatitis B e antigen (HBeAg) and virion productions. In contrast, knockdown of endogenous HNF1α expression enhanced viral gene expression and replication. This HNF1α-mediated inhibition did not depend on LHBs. Instead, HNF1α promoted the expression of NF-κB p65 and slowed p65 protein degradation, leading to nuclear accumulation of p65 and activation of the NF-κB signaling, which in turn inhibited HBV gene expression and replication. The inhibitor of the NF-κB signaling, IκBα-SR, could abrogate this HNF1α-mediated inhibition. While the dimerization domain of HNF1α was dispensable for the induction of LHBs expression, all the domains of HNF1α was required for the inhibition of HBV gene expression. Our findings identify a novel role of HNF1α in the regulation of HBV gene expression and replication.