Viral RNA in the cytoplasm of mammalian host cells is recognized by retinoic acid-inducible protein-I-like receptors (RLRs), which localize to cytoplasmic stress granules (SGs). Activated RLRs associate with the mitochondrial adaptor protein IPS-1, which activates antiviral host defense mechanisms, including type I IFN induction. It has remained unclear, however, how RLRs in SGs and IPS-1 in the mitochondrial outer membrane associate physically and engage in information transfer. In this study, we show that NUDT21, an RNA-binding protein that regulates alternative transcript polyadenylation, physically associates with IPS-1 and mediates its localization to SGs in response to transfection with polyinosinic-polycytidylic acid [poly(I:C)], a mimic of viral dsRNA. We found that despite its well-established function in the nucleus, a fraction of NUDT21 localizes to mitochondria in resting cells and becomes localized to SGs in response to poly(I:C) transfection. NUDT21 was also found to be required for efficient type I IFN induction in response to viral infection in both human HeLa cells and mouse macrophage cell line RAW264.7 cells. Our results together indicate that NUDT21 links RLRs in SGs to mitochondrial IPS-1 and thereby activates host defense responses to viral infection.

中文翻译：

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NUDT21 将线粒体 IPS-1 与含有 RLR 的压力颗粒联系起来并激活宿主抗病毒防御

哺乳动物宿主细胞细胞质中的病毒 RNA 被视黄酸诱导蛋白 I 样受体 (RLR) 识别，其定位于细胞质应激颗粒 (SG)。激活的 RLR 与线粒体衔接蛋白 IPS-1 相关联，后者激活抗病毒宿主防御机制，包括 I 型 IFN 诱导。然而，尚不清楚 SG 中的 RLR 和线粒体外膜中的 IPS-1 如何在物理上结合并参与信息传递。在这项研究中，我们展示了 NUDT21，一种调节替代转录多聚腺苷酸化的 RNA 结合蛋白，与 IPS-1 物理结合并介导其定位于 SGs，以响应聚肌苷-聚胞苷酸 [poly(I:C)] 的转染，病毒dsRNA的模拟物。我们发现，尽管它在细胞核中具有完善的功能，一部分 NUDT21 定位于静息细胞中的线粒体，并定位于 SGs 以响应 poly(I:C) 转染。还发现 NUDT21 在人 HeLa 细胞和小鼠巨噬细胞系 RAW264.7 细胞中有效诱导 I 型 IFN 以响应病毒感染。我们的结果共同表明，NUDT21 将 SG 中的 RLR 与线粒体 IPS-1 联系起来，从而激活宿主对病毒感染的防御反应。