In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNβ. This binding leads to the sequestration of IFNβ mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown.

中文翻译：

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寡腺苷酸合成酶 1 在驱动翻译关闭和保护干扰素产生方面表现出双重抗病毒机制

为了应对病毒感染，细胞如何平衡翻译关闭以限制病毒复制和诱导干扰素 (IFN) 等抗病毒成分尚不清楚。此外，IFN 诱导的寡腺苷酸合成酶 1 (OAS1) 的不同亚型如何促进这种抗病毒反应也需要进一步阐明。在这里，我们证明人类（而非小鼠）OAS1 通过其典型的 RNase L 酶活性抑制 SARS-CoV-2 复制。相比之下，小鼠和人类 OAS1 都通过与典型 RNase L 不同的机制来防止西尼罗河病毒感染激活。OAS1 结合特定 mRNA 的 AU 丰富元件 (ARE)，包括 IFNβ。这种结合导致 IFNβ mRNA 被隔离到内膜区域，从而延长半衰期并持续翻译。因此，OAS1 是一种 ARE 结合蛋白，具有两种抗病毒活性机制：驱动翻译抑制，以及保护 IFN 表达免于翻译关闭的更广泛的非规范功能。