N⁶-methyladenosine (m⁶A) is a chemical modification present in multiple RNA species and is most abundant in mRNAs. Studies on m⁶A reveal its comprehensive roles in almost every aspect of mRNA metabolism, as well as in a variety of physiological processes. Although some recent discoveries indicate that m⁶A can affect the life cycles of numerous viruses as well as the cellular antiviral immune response, the roles of m⁶A modification in type I interferon (IFN-I) signaling are still largely unknown. Here, we reveal that WT1-associated protein (WTAP), one of the m⁶A “writers”, is degraded via the ubiquitination-proteasome pathway upon activation of IFN-I signaling. With the degradation of WTAP, the m⁶A levels of IFN-regulatory factor 3 (IRF3) and interferon alpha/beta receptor subunit 1 (IFNAR1) mRNAs are reduced, leading to translational suppression of IRF3 and instability of IFNAR1 mRNA. Thus, the WTAP-IRF3/IFNAR1 axis may serve as negative feedback pathway to fine-tune the activation of IFN-I signaling, which highlights the roles of m⁶A in the antiviral response by dictating the fate of mRNAs associated with IFN-I signaling.

中文翻译：

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WTAP 的降解通过降低 IRF3 和 IFNAR1 mRNA 的 m6A 水平来阻断抗病毒反应

N ⁶ -甲基腺苷 (m ⁶ A) 是一种存在于多种 RNA 物种中的化学修饰，并且在 mRNA 中含量最高。对 m ⁶ A 的研究揭示了它在 mRNA 代谢的几乎所有方面以及多种生理过程中的综合作用。尽管最近的一些发现表明 m ⁶ A 可以影响许多病毒的生命周期以及细胞抗病毒免疫反应，但 m ⁶ A 修饰在 I 型干扰素 (IFN-I) 信号传导中的作用仍然很大程度上未知。在这里，我们揭示了 WT1 相关蛋白 (WTAP)，m ^6之一“作家”在 IFN-I 信号激活后通过泛素化-蛋白酶体途径降解。随着 WTAP 的降解，干扰素调节因子 3 ( IRF3 ) 和干扰素 α/β 受体亚基 1 ( IFNAR1 ) mRNA 的 m ⁶ A 水平降低，导致IRF3的翻译抑制和IFNAR1 mRNA的不稳定。因此，WTAP-IRF3/IFNAR1 轴可以作为负反馈途径来微调 IFN-I 信号的激活，这突出了 m ⁶ A 通过决定与 IFN-I 相关的 mRNA 的命运在抗病毒反应中的作用发信号。