DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway
DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway
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DOI：
10.1126/science.aab3291
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发表时间：
2015-10-30
期刊：
影响因子：
56.9
通讯作者：
Stetson, Daniel B.
中科院分区：
文献类型：
--
作者：
Lau, Laura;Gray, Elizabeth E.;Stetson, Daniel B.
环磷酸鸟苷-单磷酸腺苷合成酶(CGAS)检测细胞内DNA，并通过适配蛋白刺突发出信号，以启动对DNA病毒的抗病毒反应。DNA病毒能否阻止cGAS-STING通路的激活在很大程度上尚不清楚。在这里，我们鉴定了DNA肿瘤病毒的癌基因，包括来自人乳头瘤病毒(HPV)的E7和腺病毒的E1a，它们是cGAS-STING途径的有效和特异的抑制物。我们发现，这些癌蛋白的LXCXE基序对于阻断视网膜母细胞瘤肿瘤抑制因子是必不可少的，对于拮抗DNA感觉也是重要的。E1a和E7与STING结合，在人类肿瘤细胞中沉默这些癌基因可以恢复cGAS-STING途径。我们的发现揭示了宿主与病毒的冲突，这可能塑造了病毒癌基因的进化。
Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate the antiviral response to DNA viruses. Whether DNA viruses can prevent activation of the cGAS-STING pathway remains largely unknown. Here, we identify the oncogenes of the DNA tumor viruses, including E7 from human papillomavirus (HPV) and E1A from adenovirus, as potent and specific inhibitors of the cGAS-STING pathway. We show that the LXCXE motif of these oncoproteins, which is essential for blockade of the retinoblastoma tumor suppressor, is also important for antagonizing DNA sensing. E1A and E7 bind to STING, and silencing of these oncogenes in human tumor cells restores the cGAS-STING pathway. Our findings reveal a host-virus conflict that may have shaped the evolution of viral oncogenes.