Targeting m6A modification inhibits herpes virus 1 infection.
Targeting m6A modification inhibits herpes virus 1 infection.
复制标题
靶向N6 - 甲基腺苷（m6A）修饰可抑制1型疱疹病毒感染。
DOI：
10.1016/j.gendis.2021.02.004
复制
发表时间：
2022-07
期刊：
影响因子：
6.8
通讯作者：
He, Ming-Liang
中科院分区：
文献类型：
--
作者：
Feng, Zhuoying;Zhou, Fanghang;Tan, Miaomiao;Wang, Tingting;Chen, Ying;Xu, Wenwen;Li, Bin;Wang, Xin;Deng, Xin;He, Ming-Liang
1型疱疹病毒(HSV-1)的潜伏感染可能是三叉神经节的终生潜伏感染，也是阿尔茨海默病(AD)和肌萎缩侧索硬化症(ALS)的可疑病因。病毒RNA的N6-甲基腺苷(M6A)修饰是否以及如何影响病毒感染尚不清楚。在此，我们报道了HSV-1感染在感染早期促进了m6A编写器(METTL3，METTL14)和读取器(YTHDF1/2/3)的表达，而在感染后立即抑制了ERASERS(FTO，ALBKH5)的表达，以促进病毒的复制。用3-脱氮腺苷(DAA)抑制m6A修饰可显著降低病毒复制，并使病毒复制减少1000倍以上。更有趣的是，siRNA耗尽了写入者和读取者，抑制了病毒的复制和复制；而耗尽了擦除器，促进了病毒的复制和复制。沉默YTHDF3显著减少高达90%的病毒复制，导致病毒复制减少多达10倍，病毒复制减少100倍以上。通过siRNA耗尽m6A启动子METTL3(60%-70%)，相关地降低病毒复制60%-70%，并使病毒产量减少30倍以上。一致地，异位表达METTL3大大增加了病毒产量。METTL3基因敲除抑制了HSV-1中间早期和早期基因(ICP0、ICP8和UL23)和晚期基因(VP16、UL44、UL49和ICP47)的表达，而异位表达上调了这些基因的表达。我们的研究结果揭示了m6A修饰启动HSV-1早期复制的重要性。M6A修饰机制的组件，特别是m6A启动子METTL3和读取器YTHDF3，将成为抗击HSV-1感染的潜在重要目标。
The latent infection by herpes virus type 1 (HSV-1) may be lifelong in trigeminal ganglia and a suspected cause of Alzheimer's Disease (AD) and Amyotrophic lateral sclerosis (ALS). Whether and how N6-methyladenosine (m6A) modification of viral RNAs affects virus infection are poorly understood. Here, we report that HSV-1 infection enhanced the expression of m6A writers (METTL3, METTL14) and readers (YTHDF1/2/3) at the early infection stage and decreased their expression later on, while suppressed the erasers' (FTO, ALBKH5) expression immediately upon infection to facilitate viral replication. Inhibiting m6A modification by 3-deazaadenosine (DAA) significantly decreased viral replication and reduced viral reproduction over 1000 folds. More interestingly, depleting the writers and readers by siRNAs inhibited virus replication and reproduction; whereas depleting the erasers promoted viral replication and reproduction. Silencing YTHDF3 strikingly decreased viral replication by up to 90%, leading to reduction of up to 10-fold viral replication and over 100-fold virus reproduction, respectively. Depletion of m6A initiator METTL3 (by 60%–70%) by siRNA correlatedly decreased viral replication 60%–70%, and reduced virus yield over 30-fold. Consistently, ectopic expression of METTL3 largely increased virus yield. METTL3 knockdown suppressed the HSV-1 intermediate early and early genes (ICP0, ICP8 and UL23) and late genes (VP16, UL44, UL49 and ICP47); while ectopic expression of METTL3 upregulated these gene expression. Results from our study shed the lights on the importance for m6A modification to initiate HSV-1 early replication. The components of m6A modification machinery, particularly m6A initiator METTL3 and reader YTHDF3, would be potential important targets for combating HSV-1 infections.
登录
查看更多内容
影响因子：
30.3
作者：
Kennedy EM;Bogerd HP;Kornepati AV;Kang D;Ghoshal D;Marshall JB;Poling BC;Tsai K;Gokhale NS;Horner SM;Cullen BR
通讯作者：
Cullen BR
影响因子：
4.8
作者：
Kim, Geon-Woo;Imam, Hasan;Siddiqui, Aleem
通讯作者：
Siddiqui, Aleem
影响因子：
4.9
作者：
Burrel, Sonia;Deback, Claire;Boutolleau, David
通讯作者：
Boutolleau, David
影响因子：
23.9
作者：
Batista, Pedro J.;Molinie, Benoit;Wang, Jinkai;Qu, Kun;Zhang, Jiajing;Li, Lingjie;Bouley, Donna M.;Lujan, Ernesto;Haddad, Bahareh;Daneshvar, Kaveh;Carter, Ava C.;Flynn, Ryan A.;Zhou, Chan;Lim, Kok-Seong;Dedon, Peter;Wernig, Marius;Mullen, Alan C.;Xing, Yi;Giallourakis, Cosmas C.;Chang, Howard Y.
通讯作者：
Chang, Howard Y.
影响因子：
15.3
作者：
Goldsmith, K;Chen, W;Johnson, DC;Hendricks, RL
通讯作者：
Hendricks, RL