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乙型肝炎病毒 e 抗原激活细胞因子信号转导抑制因子 2 以抑制干扰素作用。

Hepatitis B Virus e Antigen Activates the Suppressor of Cytokine Signaling 2 to Repress Interferon Action.

机构信息

State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.

Life Sciences Institute, Zhejiang University, Hangzhou, China.

出版信息

Sci Rep. 2017 May 11;7(1):1729. doi: 10.1038/s41598-017-01773-6.

DOI:10.1038/s41598-017-01773-6
PMID:28496097
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5431827/
Abstract

Hepatitis B virus (HBV) infection causes acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), and eventually hepatocellular carcinoma (HCC). The presence of hepatitis B e antigen (HBeAg) in the serum generally indicates ongoing viral replication and disease progression. However, the mechanism by which HBeAg regulates HBV infection remains unclear. Interferons (IFNs) are pleiotropic cytokines that participate in host innate immunity. After binding to receptors, IFNs activate the JAK/STAT pathway to stimulate expression of IFN-stimulated genes (ISGs), leading to induction of antiviral responses. Here, we revealed that HBeAg represses IFN/JAK/STAT signaling to facilitate HBV replication. Initially, HBeAg stimulates the expression of suppressor of cytokine signaling 2 (SOCS2). Subsequently, SOCS2 impairs IFN/JAK/STAT signaling through reducing the stability of tyrosine kinase 2 (TYK2), downregulating the expression of type I and III IFN receptors, attenuating the phosphorylation and nucleus translocation of STAT1. Finally, SOCS2 inhibits the expression of ISGs, which leads to the repression of IFN action and facilitation of viral replication. These results demonstrate an important role of HBeAg in the regulation of IFN action, and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains persistent infection.

摘要

乙型肝炎病毒 (HBV) 感染可引起急性乙型肝炎 (AHB)、慢性乙型肝炎 (CHB)、肝硬化 (LC)，最终导致肝细胞癌 (HCC)。血清中乙型肝炎 e 抗原 (HBeAg) 的存在通常表明病毒复制和疾病进展持续存在。然而，HBeAg 调节 HBV 感染的确切机制尚不清楚。干扰素 (IFN) 是一种多功能细胞因子，参与宿主固有免疫。与受体结合后，IFN 激活 JAK/STAT 途径，刺激 IFN 刺激基因 (ISG) 的表达，从而诱导抗病毒反应。在这里，我们揭示了 HBeAg 通过抑制 IFN/JAK/STAT 信号通路促进 HBV 复制。最初，HBeAg 刺激细胞因子信号转导抑制因子 2 (SOCS2) 的表达。随后，SOCS2 通过降低酪氨酸激酶 2 (TYK2) 的稳定性、下调 I 型和 III 型 IFN 受体的表达、减弱 STAT1 的磷酸化和核易位来损害 IFN/JAK/STAT 信号通路。最后，SOCS2 抑制 ISG 的表达，从而抑制 IFN 作用并促进病毒复制。这些结果表明 HBeAg 在 IFN 作用的调节中起着重要作用，并提供了 HBV 抵抗 IFN 治疗和维持持续感染的可能分子机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/0e5f987bad2f/41598_2017_1773_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/50196bf23318/41598_2017_1773_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/78b0c92de123/41598_2017_1773_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/a20ea6cabcb8/41598_2017_1773_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/5e9585942678/41598_2017_1773_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/239dac5b4506/41598_2017_1773_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/4dbca005706a/41598_2017_1773_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/da02f4ab1f6e/41598_2017_1773_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/0e5f987bad2f/41598_2017_1773_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/50196bf23318/41598_2017_1773_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/78b0c92de123/41598_2017_1773_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/a20ea6cabcb8/41598_2017_1773_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/5e9585942678/41598_2017_1773_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/239dac5b4506/41598_2017_1773_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/4dbca005706a/41598_2017_1773_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/da02f4ab1f6e/41598_2017_1773_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bbdf/5431827/0e5f987bad2f/41598_2017_1773_Fig8_HTML.jpg

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