中科院武漢病毒所在EV71 m6A修飾調控病毒複製方面取得進展

導 讀

N6-methyladenosine（m6A）是一種含量最為豐富的mRNA修飾，在RNA代謝及功能中發揮重要作用，目前關於病毒m6A修飾及功能的研究較少且分子機制不清楚。近日，中國科學院武漢病毒研究所研究員關武祥和鄧菲課題組在腸道病毒71 型（EV71）m6A修飾調控病毒複製方面取得進展，相關研究以「N6-methyladenosine modification and METTL3 modulate enterovirus 71replication」為題發表在Nucleic Acids Research《核酸研究》上。研究揭示了m6A修飾影響病毒複製的分子機制，同時為病毒的防治提供了新的靶標和思路。

圖：m

6A修飾影響EV71複製

研究背景

N6-methyladenosine（m6A）是一種含量最為豐富的mRNA修飾，在RNA代謝及功能中發揮重要作用。早在40年前已經發現RNA病毒基因組含有m6A修飾，但是其功能未知，直到最近才有研究報道m6A修飾影響艾滋病病毒、乙肝病毒和寨卡病毒感染與複製。目前關於病毒m6A修飾及功能的研究較少且分子機制不清楚。

研究結果

研究表明EV71 RNA在VP、2C、3D等蛋白編碼區含有m6A修飾；EV71病毒感染改變m6A甲基化酶，去甲基化酶及識別蛋白的表達及細胞定位；改變m6A甲基化酶，去甲基化酶及識別蛋白的表達水平顯著影響病毒複製；同義突變EV71 RNA m6A位點降低病毒複製，這些結果說明m6A修飾在EV71感染中發揮重要功能。另外，該研究發現甲基化酶METTL3可與EV71 RNA依賴的RNA聚合酶（RNA-dependent RNA polymerase，RdRp）3D 相互作用，並通過增加3D的SUMO化/泛素化修飾水平增加3D蛋白穩定性及轉錄效率進而促進病毒複製。該研究不僅揭示了m6A修飾影響病毒複製的分子機制，同時為病毒的防治提供了新的靶標和思路。

本研究得到國家重點研發計劃、中科院重點部署項目、中科院高致病性病原生物學與生物安全重點實驗室開放課題等的資助。博士研究生郝好傑為論文第一作者，關武祥和鄧菲為論文通訊作者。

ABSTRACT

N6-methyladenosine (m6A) constitutes one of the most abundant internal RNA modifications and is critical for RNA metabolism and function. It has been previously reported that viral RNA contains internal m6A modifications; however, only recently the function of m6A modification in viral RNAs has been elucidated during infections of HIV, hepatitis C virus and Zika virus. In the present study, we found that enterovirus 71 (EV71) RNA undergoes m6A modification during viral infection, which alters the expression and localization of the methyltransferase and demethylase of m6A, and its binding proteins. Moreover, knockdown of m6A methyltransferase resulted in decreased EV71 replication, whereas knockdown of the demethylase had the opposite effect. Further study showed that the m6A binding proteins also participate in the regulation of viral replication. In particular, two m6A modification sites were identified in the viral genome, of which mutations resulted in decreased virus replication, suggesting that m6A modification plays an important role in EV71 replication. Notably, we found that METTL3 interacted with viral RNA-dependent RNA polymerase 3D and induced enhanced sumoylation and ubiquitination of the 3D polymerase that boosted viral replication. Taken together, our findings demonstrated that the host m6A modification complex interacts with viral proteins to modulate EV71 replication.

1.Haojie Hao Sujuan Hao Honghe Chen Zhen Chen YanfangZhang Jun Wang Hanzhong Wang Bo Zhang Jianming Qiu Fei Deng Wuxiang Guan. N6-methyladenosinemodification and METTL3 modulate enterovirus 71 replication. Nucleic AcidsResearch, gky1007.

https://doi.org/10.1093/nar/gky1007.

2.中科院武漢病毒研究所：武漢病毒所在EV71m6A修飾調控病毒複製方面取得進展

http://www.cas.cn/syky/201810/t20181030_4668087.shtml

本期編輯：Annabella

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