Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
Department of Molecular Biology, Princeton University, Princeton, NJ 08544
Proc Natl Acad Sci U S A. 2021 Nov 16;118(46). doi: 10.1073/pnas.2102134118.
Double-stranded RNA (dsRNA), a hallmark viral material that activates antiviral interferon (IFN) responses, can appear in human cells also in the absence of viruses. We identify phosphorothioate DNAs (PS DNAs) as triggers of such endogenous dsRNA (endo-dsRNA). PS DNAs inhibit decay of nuclear RNAs and induce endo-dsRNA via accumulation of high levels of intronic and intergenic inverted retroelements (IIIR). IIIRs activate endo-dsRNA responses distinct from antiviral defense programs. IIIRs do not turn on transcriptional RIG-I/MDA5/IFN signaling, but they trigger the dsRNA-sensing pathways of OAS3/RNase L and PKR. Thus, nuclear RNA decay and nuclear-cytosolic RNA sorting actively protect from these innate immune responses to self. Our data suggest that the OAS3/RNase L and PKR arms of innate immunity diverge from antiviral IFN responses and monitor nuclear RNA decay by sensing cytosolic escape of IIIRs. OAS3 provides a receptor for IIIRs, whereas RNase L cleaves IIIR-carrying introns and intergenic RNAs.
双链 RNA（dsRNA）是一种标志性的病毒物质，能激活抗病毒干扰素（IFN）反应，即使在没有病毒的情况下，也会出现在人类细胞中。我们发现硫代磷酸酯 DNA（PS DNA）是这种内源性 dsRNA（endo-dsRNA）的触发物。PS DNA 通过积累高水平的内含子和基因间反向重复元件（III Rs）来抑制核 RNA 的降解，并诱导 endo-dsRNA。III Rs 激活与抗病毒防御程序不同的内源性 dsRNA 反应。III Rs 不会开启转录 RIG-I/MDA5/IFN 信号，但会触发 OAS3/RNase L 和 PKR 的 dsRNA 感应途径。因此，核 RNA 降解和核细胞质 RNA 分选积极保护自身免受这些先天免疫反应的影响。我们的数据表明，先天免疫的 OAS3/RNase L 和 PKR 分支与抗病毒 IFN 反应不同，通过感应 III Rs 从核内逃逸到细胞质来监测核 RNA 的降解。OAS3 为 III Rs 提供了一个受体，而 RNase L 则切割携带 III Rs 的内含子和基因间 RNA。
