Subversion of innate immunity by oncoviruses, such as human papillomavirus (HPV), favors carcinogenesis because the mechanism(s) of viral immune evasion can also hamper cancer immunosurveillance. Previously, we demonstrated that high-risk (hr) HPVs trigger simultaneous epigenetic silencing of multiple effectors of innate immunity to promote viral persistence. Here, we expand on those observations and show that the HPV E7 oncoprotein upregulates the H3K9-specific methyltransferase, whose action shuts down the host innate immune response. Specifically, we demonstrate that SUV39H1 contributes to chromatin repression at the promoter regions of the viral nucleic acid sensors RIG-I and cGAS and the adaptor molecule STING in HPV-transformed cells. Inhibition of SUV39H1 leads to transcriptional activation of these genes, especially RIG-I, followed by increased beta interferon (IFN-β) and IFN-λ1 production after poly(dA·dT) or RIG-I agonist M8 transfection. Collectively, our findings provide new evidence that the E7 oncoprotein plays a central role in dampening host innate immunity and raise the possibility that targeting the downstream effector SUV39H1 or the RIG-I pathway is a viable strategy to treat viral and neoplastic disease.IMPORTANCE High-risk HPVs are major viral human carcinogens responsible for approximately 5% of all human cancers. The growth of HPV-transformed cells depends on the ability of viral oncoproteins to manipulate a variety of cellular circuits, including those involved in innate immunity. Here, we show that one of these strategies relies on E7-mediated transcriptional activation of the chromatin repressor SUV39H1, which then promotes epigenetic silencing of RIG-I, cGAS, and STING genes, thereby shutting down interferon secretion in HPV-transformed cells. Pharmacological or genetic inhibition of SUV39H1 restored the innate response in HPV-transformed cells, mostly through activation of RIG-I signaling. We also show that IFN production upon transfection of poly(dA·dT) or the RIG-I agonist M8 predominantly occurs through RIG-I signaling. Altogether, the reversible nature of the modifications associated with E7-mediated SUV39H1 upregulation provides a rationale for the design of novel anticancer and antiviral therapies targeting these molecules.

中文翻译：

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人乳头瘤病毒 E7 癌蛋白通过 SUV39H1 介导的免疫传感器基因表观遗传沉默颠覆宿主先天免疫。


人乳头瘤病毒 (HPV) 等肿瘤病毒对先天免疫的破坏有利于致癌，因为病毒免疫逃避的机制也会阻碍癌症免疫监视。此前，我们证明高危 (hr) HPV 会同时触发先天免疫的多个效应器的表观遗传沉默，从而促进病毒持续存在。在这里，我们扩展了这些观察结果，并表明 HPV E7 癌蛋白上调 H3K9 特异性甲基转移酶，其作用会关闭宿主先天免疫反应。具体来说，我们证明SUV39H1有助于HPV转化细胞中病毒核酸传感器RIG-I和cGAS以及接头分子STING的启动子区域的染色质抑制。抑制 SUV39H1 会导致这些基因（尤其是 RIG-I）的转录激活，然后在聚（dA·dT）或 RIG-I 激动剂 M8 转染后增加 β 干扰素 (IFN-β) 和 IFN-λ1 的产生。总的来说，我们的研究结果提供了新的证据，证明 E7 癌蛋白在抑制宿主先天免疫中发挥着核心作用，并提出了靶向下游效应子 SUV39H1 或 RIG-I 途径是治疗病毒和肿瘤疾病的可行策略的可能性。危险 HPV 是主要的病毒性人类致癌物，约占所有人类癌症的 5%。 HPV 转化细胞的生长取决于病毒癌蛋白操纵多种细胞回路的能力，包括那些涉及先天免疫的细胞回路。在这里，我们表明其中一种策略依赖于 E7 介导的染色质阻遏蛋白 SUV39H1 的转录激活，然后促进 RIG-I、cGAS 和 STING 基因的表观遗传沉默，从而关闭 HPV 转化细胞中的干扰素分泌。 SUV39H1 的药理学或基因抑制可恢复 HPV 转化细胞的先天反应，主要是通过激活 RIG-I 信号传导。我们还表明，转染聚（dA·dT）或 RIG-I 激动剂 M8 时，IFN 的产生主要通过 RIG-I 信号传导发生。总而言之，与 E7 介导的 SUV39H1 上调相关的修饰的可逆性质为设计针对这些分子的新型抗癌和抗病毒疗法提供了理论基础。