Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, China.
Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao 266237, China.
Proc Natl Acad Sci U S A. 2024 Jul 30;121(31):e2409233121. doi: 10.1073/pnas.2409233121. Epub 2024 Jul 24.
Invertebrates mainly rely on sequence-specific RNA interference (RNAi) to resist viral infections. Increasing studies show that double-stranded RNA (dsRNA) can induce sequence-independent protection and that Dicer-2, the key RNAi player that cleaves long dsRNA into small interfering RNA (siRNA), is necessary for this protection. However, how this protection occurs remains unknown. Herein, we report that it is caused by adenosine triphosphate (ATP)-hydrolysis accompanying the dsRNA-cleavage. Dicer-2 helicase domain is ATP-dependent; therefore, the cleavage consumes ATP. ATP depletion activates adenosine monophosphate-activated protein kinase (Ampk) and induces nuclear localization of Fork head box O (FoxO), a key transcriptional factor for dsRNA-induced genes. siRNAs that do not require processing cannot activate the transcriptional response. This study reveals a unique nonspecific antiviral mechanism other than the specific RNAi in shrimp. This mechanism is functionally similar to, but mechanistically different from, the dsRNA-activated antiviral response in vertebrates and suggests an interesting evolution of innate antiviral immunity.
无脊椎动物主要依赖序列特异性 RNA 干扰 (RNAi) 来抵抗病毒感染。越来越多的研究表明，双链 RNA (dsRNA) 可以诱导非序列依赖性保护，而 Dicer-2 是一种关键的 RNAi 酶，可将长 dsRNA 切割成小干扰 RNA (siRNA)，这对于这种保护是必需的。然而，这种保护是如何发生的仍然未知。在此，我们报告称，这是由伴随 dsRNA 切割的三磷酸腺苷 (ATP) 水解引起的。Dicer-2 解旋酶结构域依赖于 ATP；因此，切割会消耗 ATP。ATP 耗竭会激活单磷酸腺苷激活的蛋白激酶 (Ampk)，并诱导 Fork head box O (FoxO) 的核定位，FoxO 是 dsRNA 诱导基因的关键转录因子。不需要加工的 siRNA 不能激活转录反应。这项研究揭示了虾中除特定 RNAi 之外的一种独特的非特异性抗病毒机制。这种机制在功能上类似于脊椎动物中的 dsRNA 激活抗病毒反应，但在机制上不同，提示先天抗病毒免疫的有趣进化。
