Type I interferons (IFN) induce hundreds of IFN-stimulated genes (ISGs) in response to viral infection. These ISGs require strict regulation for an efficient and controlled antiviral response, but post-transcriptional controls of these genes have not been well defined. Here, we identify a new role for the RNA base modification N6-methyladenosine (m6A) in the regulation of ISGs. Using ribosome profiling and quantitative mass spectrometry, coupled with m6A-immunoprecipitation and sequencing, we identified a subset of ISGs, including IFITM1, whose translation is enhanced by m6A and the m6A methyltransferase proteins METTL3 and METTL14. We further determined that the m6A reader YTHDF1 increases the expression of IFITM1 in an m6A binding-dependent manner. Importantly, we found that the m6A methyltransferase complex promotes the antiviral activity of type I IFN. Thus, these studies identify m6A as a post-transcriptional control of ISG translation during the type I IFN response for antiviral restriction.

中文翻译：

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N6-甲基腺苷对抗病毒基因表达的转录后调控

响应病毒感染，I型干扰素（IFN）诱导数百种IFN刺激基因（ISG）。这些ISG需要严格调节才能有效控制抗病毒反应，但是对这些基因的转录后控制尚未明确定义。在这里，我们确定RNA修饰N6-甲基腺苷（m6A）在ISGs调控中的新作用。使用核糖体谱分析和定量质谱，结合m6A免疫沉淀和测序，我们鉴定了ISG的一个子集，包括IFITM1，其翻译被m6A和m6A甲基转移酶蛋白METTL3和METTL14增强。我们进一步确定，m6A阅读器YTHDF1以m6A结合依赖性方式增加了IFITM1的表达。重要的，我们发现m6A甲基转移酶复合物可促进I型IFN的抗病毒活性。因此，这些研究将m6A识别为抗病毒限制的I型IFN反应期间ISG翻译的转录后控制。