Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication

ABSTRACT The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an ongoing global public crisis. Although viral RNA modification has been reported based on the transcriptome architecture, the types and functions of RNA modification are still u...

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Autores principales: Xueyan Zhang, Haojie Hao, Li Ma, Yecheng Zhang, Xiao Hu, Zhen Chen, Di Liu, Jianhui Yuan, Zhangli Hu, Wuxiang Guan
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Publicado: American Society for Microbiology 2021
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spelling oai:doaj.org-article:ad83539be7be4937a2a87f81497470d72021-11-10T18:37:52ZMethyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication10.1128/mBio.01067-212150-7511https://doaj.org/article/ad83539be7be4937a2a87f81497470d72021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01067-21https://doaj.org/toc/2150-7511ABSTRACT The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an ongoing global public crisis. Although viral RNA modification has been reported based on the transcriptome architecture, the types and functions of RNA modification are still unknown. In this study, we evaluated the roles of RNA N6-methyladenosine (m6A) modification in SARS-CoV-2. Our methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and Nanopore direct RNA sequencing (DRS) analysis showed that SARS-CoV-2 RNA contained m6A modification. Moreover, SARS-CoV-2 infection not only increased the expression of methyltransferase-like 3 (METTL3) but also altered its distribution. Modification of METTL3 expression by short hairpin RNA or plasmid transfection for knockdown or overexpression, respectively, affected viral replication. Furthermore, the viral key protein RdRp interacted with METTL3, and METTL3 was distributed in both the nucleus and cytoplasm in the presence of RdRp. RdRp appeared to modulate the sumoylation and ubiquitination of METTL3 via an unknown mechanism. Taken together, our findings demonstrated that the host m6A modification complex interacted with viral proteins to modulate SARS-CoV-2 replication. IMPORTANCE Internal chemical modifications of viral RNA play key roles in the regulation of viral replication and gene expression. Although potential internal modifications have been reported in SARS-CoV-2 RNA, the function of the SARS-CoV-2 N6-methyladenosine (m6A) modification in the viral life cycle is unclear. In the current study, we demonstrated that SARS-CoV-2 RNA underwent m6A modification by host m6A machinery. SARS-CoV-2 infection altered the expression pattern of methyltransferases and demethylases, while the expression level of methyltransferase-like 3 (METTL3) and fat mass and obesity-associated protein (FTO) was linked to the viral replication. Further study showed that METTL3 interacted with viral RNA polymerase RNA-dependent RNA polymerase (RdRp), which influenced not only the distribution but also the posttranslational modification of METTL3. Our study provided evidence that host m6A components interacted with viral proteins to modulate viral replication.Xueyan ZhangHaojie HaoLi MaYecheng ZhangXiao HuZhen ChenDi LiuJianhui YuanZhangli HuWuxiang GuanAmerican Society for Microbiologyarticlemethyltransferase-like 3respiratory syndrome coronavirus-2N6-methyladenosineviral replicationMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution DOAJ
collection DOAJ
language EN
topic methyltransferase-like 3
respiratory syndrome coronavirus-2
N6-methyladenosine
viral replication
Microbiology
QR1-502
spellingShingle methyltransferase-like 3
respiratory syndrome coronavirus-2
N6-methyladenosine
viral replication
Microbiology
QR1-502
Xueyan Zhang
Haojie Hao
Li Ma
Yecheng Zhang
Xiao Hu
Zhen Chen
Di Liu
Jianhui Yuan
Zhangli Hu
Wuxiang Guan
Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication
description ABSTRACT The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an ongoing global public crisis. Although viral RNA modification has been reported based on the transcriptome architecture, the types and functions of RNA modification are still unknown. In this study, we evaluated the roles of RNA N6-methyladenosine (m6A) modification in SARS-CoV-2. Our methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and Nanopore direct RNA sequencing (DRS) analysis showed that SARS-CoV-2 RNA contained m6A modification. Moreover, SARS-CoV-2 infection not only increased the expression of methyltransferase-like 3 (METTL3) but also altered its distribution. Modification of METTL3 expression by short hairpin RNA or plasmid transfection for knockdown or overexpression, respectively, affected viral replication. Furthermore, the viral key protein RdRp interacted with METTL3, and METTL3 was distributed in both the nucleus and cytoplasm in the presence of RdRp. RdRp appeared to modulate the sumoylation and ubiquitination of METTL3 via an unknown mechanism. Taken together, our findings demonstrated that the host m6A modification complex interacted with viral proteins to modulate SARS-CoV-2 replication. IMPORTANCE Internal chemical modifications of viral RNA play key roles in the regulation of viral replication and gene expression. Although potential internal modifications have been reported in SARS-CoV-2 RNA, the function of the SARS-CoV-2 N6-methyladenosine (m6A) modification in the viral life cycle is unclear. In the current study, we demonstrated that SARS-CoV-2 RNA underwent m6A modification by host m6A machinery. SARS-CoV-2 infection altered the expression pattern of methyltransferases and demethylases, while the expression level of methyltransferase-like 3 (METTL3) and fat mass and obesity-associated protein (FTO) was linked to the viral replication. Further study showed that METTL3 interacted with viral RNA polymerase RNA-dependent RNA polymerase (RdRp), which influenced not only the distribution but also the posttranslational modification of METTL3. Our study provided evidence that host m6A components interacted with viral proteins to modulate viral replication.
format article
author Xueyan Zhang
Haojie Hao
Li Ma
Yecheng Zhang
Xiao Hu
Zhen Chen
Di Liu
Jianhui Yuan
Zhangli Hu
Wuxiang Guan
author_facet Xueyan Zhang
Haojie Hao
Li Ma
Yecheng Zhang
Xiao Hu
Zhen Chen
Di Liu
Jianhui Yuan
Zhangli Hu
Wuxiang Guan
author_sort Xueyan Zhang
title Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication
title_short Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication
title_full Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication
title_fullStr Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication
title_full_unstemmed Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication
title_sort methyltransferase-like 3 modulates severe acute respiratory syndrome coronavirus-2 rna n6-methyladenosine modification and replication
publisher American Society for Microbiology
publishDate 2021
url https://doaj.org/article/ad83539be7be4937a2a87f81497470d7
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