NUDT21 Links Mitochondrial IPS-1 to RLR-Containing Stress Granules and Activates Host Antiviral Defense
NUDT21 Links Mitochondrial IPS-1 to RLR-Containing Stress Granules and Activates Host Antiviral Defense
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DOI：
10.4049/jimmunol.2000306
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发表时间：
2021-01-01
影响因子：
4.4
通讯作者：
Gotoh, Yukiko
中科院分区：
文献类型：
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作者：
Aoyama-Ishiwatari, Saeko;Okazaki, Tomohiko;Gotoh, Yukiko
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，该受体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，后者激活抗病毒宿主防御机制，包括 I 型 IFN 诱导。然而，目前尚不清楚SG中的RLR和线粒体外膜中的IPS-1如何物理结合并参与信息传递。在这项研究中，我们发现 NUDT21（一种调节替代转录物多聚腺苷酸化的 RNA 结合蛋白）与 IPS-1 发生物理关联，并响应病毒 dsRNA 模拟物聚肌胞多胞苷酸 [poly(I:C)] 的转染，介导其定位到 SG。我们发现，尽管 NUDT21 在细胞核中具有完善的功能，但仍有一部分 NUDT21 定位于静息细胞中的线粒体，并响应聚 (I:C) 转染而定位于 SG。还发现 NUDT21 是人类 HeLa 细胞和小鼠巨噬细胞系 RAW264.7 细胞响应病毒感染时有效诱导 I 型 IFN 所必需的。我们的结果共同表明，NUDT21 将 SG 中的 RLR 与线粒体 IPS-1 连接起来，从而激活宿主对病毒感染的防御反应。
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.