Degradation of WTAP blocks antiviral responses by reducing the m(6) A levels of IRF3 and IFNAR1 mRNA.
Degradation of WTAP blocks antiviral responses by reducing the m(6) A levels of IRF3 and IFNAR1 mRNA.
复制标题
WTAP 的降解通过降低 IRF3 和 IFNAR1 mRNA 的 m(6)A 水平来阻断抗病毒反应
DOI：
10.15252/embr.202052101
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发表时间：
2021-11-04
期刊：
影响因子：
7.7
通讯作者：
Xu A
中科院分区：
文献类型：
--
作者：
Ge Y;Ling T;Wang Y;Jia X;Xie X;Chen R;Chen S;Yuan S;Xu A
N-6-甲基腺苷（m6 A）是一种存在于多种RNA中的化学修饰，在mRNA中含量最高。对m6 A的研究揭示了它在mRNA代谢的几乎每个方面以及在各种生理过程中的综合作用。尽管最近的一些发现表明m6 A可以影响许多病毒的生命周期以及细胞抗病毒免疫应答，但m6 A修饰在I型干扰素（IFN-I）信号传导中的作用在很大程度上仍然未知。在这里，我们揭示了WT 1相关蛋白（WTAP），m6 A“作家”之一，在IFN-I信号转导激活后通过泛素化-蛋白酶体途径降解。随着WTAP的降解，IFN-调节因子3（IRF 3）和干扰素α/β受体亚基1（IFNAR 1）mRNA的m6 A水平降低，导致IRF 3的翻译抑制和IFNAR 1 mRNA的不稳定性。因此，WTAP-IRF 3/IFNAR 1轴可能作为负反馈途径来微调IFN-I信号传导的激活，这通过决定与IFN-I信号传导相关的mRNA的命运来强调m6 A在抗病毒反应中的作用。病毒感染后蛋白酶体介导的m6 A writer WTAP降解降低了IRF 3和IFNAR 1 mRNA上的m6 A水平，随后降低了它们的蛋白质输出，从而阻断了IFN-I介导的抗病毒反应。
N 6‐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. Proteasome mediated degradation of the m6A writer WTAP upon viral infection reduces m6A levels on IRF3 and IFNAR1 mRNAs and subsequently their protein output, thereby blocking IFN‐I‐mediated antiviral responses.