Nucleic acid-based systems play important roles in antiviral defense, including CRISPR/Cas that adopts RNA-guided DNA cleavage to prevent DNA phage infection and RNA interference (RNAi) that employs RNA-guided RNA cleavage to defend against RNA virus infection. Here, we report a novel type of nucleic acid-based antiviral system that exists in mouse embryonic stem cells (mESCs), which suppresses RNA virus infection by DNA-mediated RNA cleavage. We found that the viral RNA of encephalomyocarditis virus can be reverse transcribed into complementary DNA (vcDNA) by the reverse transcriptase (RTase) encoded by endogenous retrovirus-like elements in mESCs. The vcDNA is negative-sense single-stranded and forms DNA/RNA hybrid with viral RNA. The viral RNA in the heteroduplex is subsequently destroyed by cellular RNase H1, leading to robust suppression of viral growth. Furthermore, either inhibition of the RTase activity or depletion of endogenous RNase H1 results in the promotion of virus proliferation. Altogether, our results provide intriguing insights into the antiviral mechanism of mESCs and the antiviral function of endogenized retroviruses and cellular RNase H. Such a natural nucleic acid-based antiviral mechanism in mESCs is referred to as ERASE (endogenous RTase/RNase H-mediated antiviral system), which is an addition to the previously known nucleic acid-based antiviral mechanisms including CRISPR/Cas in bacteria and RNAi in plants and invertebrates.

基于核酸的系统在抗病毒防御中发挥着重要作用，包括采用 RNA 引导的 DNA 切割来防止 DNA 噬菌体感染的 CRISPR/Cas 和采用 RNA 引导的 RNA 切割来防御 RNA 病毒感染的 RNA 干扰 (RNAi)。在这里，我们报告了一种存在于小鼠胚胎干细胞 (mESC) 中的新型基于核酸的抗病毒系统，它通过 DNA 介导的 RNA 裂解抑制 RNA 病毒感染。我们发现脑心肌炎病毒的病毒 RNA 可以通过 mESC 中内源性逆转录病毒样元件编码的逆转录酶 (RTase) 逆转录成互补 DNA (vcDNA)。vcDNA 为负义单链，与病毒 RNA 形成 DNA/RNA 杂合体。异源双链体中的病毒 RNA 随后被细胞核糖核酸酶 H1 破坏，导致对病毒生长的强烈抑制。此外，RTase 活性的抑制或内源性 RNase H1 的消耗都会促进病毒增殖。总而言之，我们的结果为 mESC 的抗病毒机制以及内源性逆转录病毒和细胞 RNase H 的抗病毒功能提供了有趣的见解。mESC 中这种基于天然核酸的抗病毒机制被称为 ERASE（内源性 RTase/RNase H 介导的抗病毒系统），这是对先前已知的基于核酸的抗病毒机制的补充，包括细菌中的 CRISPR/Cas 和植物和无脊椎动物中的 RNAi。