TMEM2 inhibits hepatitis B virus infection in HepG2 and HepG2.2.15 cells by activating the JAK-STAT signaling pathway.
TMEM2 inhibits hepatitis B virus infection in HepG2 and HepG2.2.15 cells by activating the JAK-STAT signaling pathway.
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TMEM2通过激活JAK-STAT信号通路抑制HepG2和HepG2.2.15细胞中的乙型肝炎病毒感染
DOI：
10.1038/cddis.2016.146
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发表时间：
2016-06-02
影响因子：
9
通讯作者：
Peng L
中科院分区：
文献类型：
--
作者：
Zhu X;Xie C;Li YM;Huang ZL;Zhao QY;Hu ZX;Wang PP;Gu YR;Gao ZL;Peng L
我们先前已经观察到TMEM 2在慢性B型肝炎病毒（HBV）感染患者的肝组织中以及在具有HBV基因组DNA的HepG 2.2.15细胞中下调。在本研究中，我们研究了TMEM 2在HepG 2和HepG2.2.15中在HBV感染HepG 2和HepG2.2.15过程中的作用和机制。使用慢病毒载体建立具有稳定TMEM 2敲低的HepG 2 shTMEM 2细胞和具有稳定TMEM 2过表达的HepG 2 TMEM 2和HepG2.2.15 TMEM 2细胞。我们观察到TMEM 2在HBV感染的肝组织和HepG2.2.15细胞中表达减少。与初始HepG 2细胞相比，HepG 2 shTMEM 2细胞中HBsAg、HBcAg、HBV DNA和HBV cccDNA水平显著升高，但在HepG 2 TMEM 2和HepG2.2.15 TMEM 2细胞中降低。Western印迹结果显示，JAK-STAT信号通路在HepG 2 shTMEM 2细胞中被抑制，而在HepG 2 TMEM 2和HepG2.2.15 TMEM 2细胞中被激活。此外，在TMEM 2沉默细胞（HepG 2 shTMEM 2细胞）和TMEM 2过表达细胞（HepG 2 TMEM 2和HepG2.2.15 TMEM 2细胞）中分别观察到抗病毒蛋白MxA和OAS 1的表达减少和增加。干扰素调节因子9（IRF 9）的表达不受TMEM 2的影响。然而，我们发现TMEM 2的过表达和敲低分别促进和抑制IRF 9输入细胞核。荧光素酶报告基因分析表明，IRF 9核转位影响干扰素刺激的反应元件的活动。干扰素预处理可显著增强TMEM 2对HepG 2 shTMEM 2细胞HBV感染的抑制作用，而JAK 1抑制剂预处理可显著抑制HepG2.2.15 TMEM 2细胞HBV感染。TMEM 2通过激活JAK-STAT信号通路抑制HepG 2和HepG2.2.15中的HBV感染。
We have previously observed the downregulation of TMEM2 in the liver tissue of patients with chronic hepatitis B virus (HBV) infection and in HepG2.2.15 cells with HBV genomic DNA. In the present study, we investigated the role and mechanism of TMEM2 in HepG2 and HepG2.2.15 during HBV infection HepG2 and HepG2.2.15. HepG2 shTMEM2 cells with stable TMEM2 knockdown and HepG2 TMEM2 and HepG2.2.15 TMEM2 cells with stable TMEM2 overexpression were established using lentivirus vectors. We observed reduced expression of TMEM2 in HBV-infected liver tissues and HepG2.2.15 cells. HBsAg, HBcAg, HBV DNA, and HBV cccDNA levels were significantly increased in HepG2 shTMEM2 cells but decreased in HepG2 TMEM2 and HepG2.2.15 TMEM2 cells compared with naive HepG2 cells. On the basis of the western blotting results, the JAK–STAT signaling pathway was inhibited in HepG2 shTMEM2 cells but activated in HepG2 TMEM2 and HepG2.2.15 TMEM2 cells. In addition, reduced and increased expression of the antiviral proteins MxA and OAS1 was observed in TMEM2-silenced cells (HepG2 shTMEM2 cells) and TMEM2-overexpressing cells (HepG2 TMEM2 and HepG2.2.15 TMEM2 cells), respectively. The expression of Interferon regulatory factor 9 (IRF9) was not affected by TMEM2. However, we found that overexpression and knockdown of TMEM2, respectively, promoted and inhibited importation of IRF9 into nuclei. The luciferase reporter assay showed that IRF9 nuclear translocation affected interferon-stimulated response element activities. In addition, the inhibitory effects of TMEM2 on HBV infection in HepG2 shTMEM2 cells was significantly enhanced by pre-treatment with interferon but significantly inhibited in HepG2.2.15 TMEM2 cells by pre-treatment with JAK1 inhibitor. TMEM2 inhibits HBV infection in HepG2 and HepG2.2.15 by activating the JAK–STAT signaling pathway.
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