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Degradation of WTAP blocks antiviral responses by reducing the m6A levels of IRF3 and IFNAR1 mRNA
EMBO Reports ( IF 6.5 ) Pub Date : 2021-09-01 , DOI: 10.15252/embr.202052101
Yong Ge 1, 2 , Tao Ling 1, 2 , Yao Wang 1, 3 , Xin Jia 1, 4 , Xiongmei Xie 1 , Rong Chen 1, 2 , Shangwu Chen 1 , Shaochun Yuan 1, 2, 5 , Anlong Xu 1, 3
Affiliation  

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:

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。
更新日期:2021-11-04
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