Epidermal Growth Factor Receptor Signaling Impairs the Antiviral Activity of Interferon-Alpha
Epidermal Growth Factor Receptor Signaling Impairs the Antiviral Activity of Interferon-Alpha
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DOI：
10.1002/hep.26404
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发表时间：
2013-10-01
期刊：
影响因子：
13.5
通讯作者：
Baumert, Thomas F.
中科院分区：
文献类型：
--
作者：
Lupberger, Joachim;Duong, Francois H. T.;Baumert, Thomas F.
干扰素-α（IFN-α）通过信号转导和转录激活蛋白（STAT）信号传导以及IFN应答基因（IRGs）的表达而发挥其抗病毒活性。已显示病毒感染导致表皮生长因子受体（EGFR）的活化，表皮生长因子受体是包括丙型肝炎病毒在内的几种病毒使用的宿主细胞进入因子。然而，EGFR激活对细胞抗病毒应答的影响尚不清楚。在这里，我们揭示了EGFR和IFN信号之间的串扰，对基于IFN的疗法具有治疗效果，并且与病毒逃避和IFN抗性具有功能相关性。我们表明，结合IFN-γ与EGFR抑制剂，厄洛替尼，增强了每种化合物的抗病毒作用，在一个高度协同的方式。协同作用的程度与在厄洛替尼存在下STAT 3磷酸化降低相关，而STAT 1磷酸化不受影响。此外，STAT 3磷酸化减少与厄洛替尼存在下细胞因子信号传导抑制因子3（SOCS 3）的表达增强以及IRGs、含自由基S-腺苷甲硫氨酸结构域2和粘病毒抗性蛋白1的表达增强相关。此外，EGFR刺激减少了STAT 1的二聚化，但没有减少磷酸化，这表明EGFR与IFN信号的串扰在结合DNA的水平上作用于STAT。结论：我们的研究结果支持一个模型，其中抑制EGFR信号传导损害STAT 3磷酸化，导致增强IRG表达和抗病毒活性。这些数据揭示了EGFR信号在IFN-γ抗病毒活性中的新作用，并为提高基于IFN-γ的抗病毒治疗的疗效开辟了新途径。（肝病学2013;58：1225-1235）
Interferon-alpha (IFN-) exhibits its antiviral activity through signal transducer and activator of transcription protein (STAT) signaling and the expression of IFN response genes (IRGs). Viral infection has been shown to result in activation of epidermal growth factor receptor (EGFR)a host cell entry factor used by several viruses, including hepatitis C virus. However, the effect of EGFR activation for cellular antiviral responses is unknown. Here, we uncover cross-talk between EGFR and IFN- signaling that has a therapeutic effect on IFN--based therapies and functional relevance for viral evasion and IFN resistance. We show that combining IFN- with the EGFR inhibitor, erlotinib, potentiates the antiviral effect of each compound in a highly synergistic manner. The extent of the synergy correlated with reduced STAT3 phosphorylation in the presence of erlotinib, whereas STAT1 phosphorylation was not affected. Furthermore, reduced STAT3 phosphorylation correlated with enhanced expression of suppressors of cytokine signaling 3 (SOCS3) in the presence of erlotinib and enhanced expression of the IRGs, radical S-adenosyl methionine domain containing 2 and myxovirus resistance protein 1. Moreover, EGFR stimulation reduced STAT1 dimerization, but not phosphorylation, indicating that EGFR cross-talk with IFN signaling acts on the STATs at the level of binding DNA. Conclusions: Our results support a model where inhibition of EGFR signaling impairs STAT3 phosphorylation, leading to enhanced IRG expression and antiviral activity. These data uncover a novel role of EGFR signaling in the antiviral activity of IFN- and open new avenues of improving the efficacy of IFN--based antiviral therapies. (Hepatology 2013;58:1225-1235)