Methyltransferase-Like Protein 14 Attenuates Mitochondrial Antiviral Signaling Protein Expression to Negatively Regulate Antiviral Immunity via N(6) -methyladenosine Modification.
Methyltransferase-Like Protein 14 Attenuates Mitochondrial Antiviral Signaling Protein Expression to Negatively Regulate Antiviral Immunity via N(6) -methyladenosine Modification.
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甲基转移酶 - 类似蛋白 14 通过 N 6 - 甲基腺苷修饰减弱线粒体抗病毒信号蛋白表达，从而负调节抗病毒免疫
DOI：
10.1002/advs.202100606
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Gao C
中科院分区：
文献类型：
--
作者：
Qin F;Cai B;Zhao J;Zhang L;Zheng Y;Liu B;Gao C
线粒体抗病毒信号（MAVS）蛋白是RNA信号通路中的核心信号衔接蛋白。因此，对MAVS表达的适度调控对于针对RNA病毒感染的抗病毒免疫至关重要。然而，MAVS在mRNA水平尤其是转录后水平的表达调控机制尚不明确。本文报道，MAVS的mRNA通过甲基转移酶样蛋白14（METTL14）发生N6 - 甲基腺苷（m6A）修饰，这导致MAVS mRNA快速周转。敲低或缺失METTL14可提高MAVS mRNA的稳定性，以及在应对RNA病毒时TBK1/IRF3的下游磷酸化和干扰素-β的产生。与野生型小鼠相比，杂合子Mettl14 +/−小鼠对RNA病毒感染的耐受性更强。作者的研究结果揭示了一种通过m6A修饰在转录后调控MAVS转录本稳定性的新机制。
本研究表明，METTL14通过对MAVS mRNA的m6A修饰，在维甲酸诱导基因I样受体（RLR）介导的先天性抗病毒反应中发挥重要作用。METTL14的缺失可提高MAVS mRNA的稳定性以及在应对RNA病毒时干扰素-β的产生。METTL14对MAVS转录本的m6A修饰负向调控RLR诱导的先天性免疫。
Mitochondrial antiviral signaling (MAVS) protein is the core signaling adaptor in the RNA signaling pathway. Thus, appropriate regulation of MAVS expression is essential for antiviral immunity against RNA virus infection. However, the regulation of MAVS expression at the mRNA level especially at the post transcriptional level is not well‐defined. Here, it is reported that the MAVS mRNA undergoes N6‐methyladenosine (m6A) modification through methyltransferase‐like protein 14 (METTL14), which leads to a fast turnover of MAVS mRNA. Knockdown or deficiency of METTL14 increases MAVS mRNA stability, and downstream phosphorylation of TBK1/IRF3 and interferon‐β production in response to RNA viruses. Compared to wild‐type mice, heterozygotes Mettl14 +/− mice better tolerate RNA virus infection. The authors' findings unveil a novel mechanism to regulate the stability of MAVS transcripts post‐transcriptionally through m6A modification. This study reveals that METTL14 plays an important role in the retinoic acid‐inducible gene‐I‐like receptors (RLR)‐mediated innate antiviral response via m6A modification of MAVS mRNA. Deficiency of METTL14 increases MAVS mRNA stability and interferon‐β production in response to RNA viruses. m6A modification on MAVS transcripts by METTL14 negatively regulates the RLR‐induced innate immunity.
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