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N-甲基腺苷对人呼吸道合胞病毒复制起负调控作用。

N -Methyladenosine Negatively Regulates Human Respiratory Syncytial Virus Replication.

作者信息

Figueroa Fabian, Vega-Gibson Alonso, Catrileo Joseline, Gaete-Argel Aracelly, Riquelme-Barrios Sebastian, Alonso-Palomares Luis Antonio, Tapia Lorena I, Valiente-Echeverría Fernando, Soto-Rifo Ricardo, Acevedo Monica L

机构信息

Laboratory of Molecular and Cellular Virology, Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.

HIV/AIDS Workgroup, Faculty of Medicine, Universidad de Chile, Santiago, Chile.

出版信息

Front Cell Dev Biol. 2021 Oct 4;9:739445. doi: 10.3389/fcell.2021.739445. eCollection 2021.

DOI:10.3389/fcell.2021.739445
PMID:34671602
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8521026/
Abstract

N-methyladenosine (mA) is the most abundant internal modification described in eukaryotic mRNA and several viral RNA including human respiratory syncytial virus (HRSV). Here, we evaluated the impact of mA writers, erasers and readers on HRSV genomic RNA accumulation and inclusion bodies assembly during viral replication. We observed that the METTL3/METTL14 mA writer complex plays a negative role in HRSV protein synthesis and viral titers, while mA erasers FTO and ALKBH5 had the opposite effect. We also observed that mA readers YTHDF1-3 bind to the viral genomic RNA inducing a decrease in its intracellular levels and thus, inhibiting viral replication. Finally, we observed that overexpression of YTHDFs proteins caused a decrease in the size of inclusion bodies (IBs), accompanied by an increase in their number. METTL3 knockdown cells showed an opposite effect indicating that the dynamics of IBs assembly and coalescence are strongly affected by mA readers in a mechanism dependent on mA writers. Taken together, our results demonstrated that the mA modification negatively affects HRSV replication, possibly through a mechanism involving the assembly of inclusion bodies, the main factories of viral genomic RNA synthesis.

摘要

N6-甲基腺苷（mA）是真核生物mRNA以及包括人呼吸道合胞病毒（HRSV）在内的几种病毒RNA中描述的最丰富的内部修饰。在此，我们评估了mA写入酶、擦除酶和读取蛋白对HRSV基因组RNA积累以及病毒复制过程中包涵体组装的影响。我们观察到，METTL3/METTL14 mA写入酶复合物在HRSV蛋白质合成和病毒滴度方面发挥负面作用，而mA擦除酶FTO和ALKBH5则具有相反的效果。我们还观察到，mA读取蛋白YTHDF1-3与病毒基因组RNA结合，导致其细胞内水平降低，从而抑制病毒复制。最后，我们观察到YTHDFs蛋白的过表达导致包涵体（IBs）尺寸减小，同时数量增加。METTL3敲低细胞表现出相反的效果，表明IBs组装和融合的动力学在依赖于mA写入酶的机制中受到mA读取蛋白的强烈影响。综上所述，我们的结果表明，mA修饰可能通过涉及包涵体组装（病毒基因组RNA合成的主要场所）的机制对HRSV复制产生负面影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8df5/8521026/69f68afa506f/fcell-09-739445-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8df5/8521026/59853b31234f/fcell-09-739445-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8df5/8521026/cfe887a94355/fcell-09-739445-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8df5/8521026/8d2b33ffdf95/fcell-09-739445-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8df5/8521026/69f68afa506f/fcell-09-739445-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8df5/8521026/59853b31234f/fcell-09-739445-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8df5/8521026/cfe887a94355/fcell-09-739445-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8df5/8521026/8d2b33ffdf95/fcell-09-739445-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8df5/8521026/69f68afa506f/fcell-09-739445-g004.jpg

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