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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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2021-08-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01067-21 |
| _version_ | 1818985894517932032 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T18:42:09Z |
| format | Article |
| id | doaj.art-ad83539be7be4937a2a87f81497470d7 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-20T18:42:09Z |
| publishDate | 2021-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-ad83539be7be4937a2a87f81497470d72022-12-21T19:29:46ZengAmerican Society for MicrobiologymBio2150-75112021-08-0112410.1128/mBio.01067-21Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and ReplicationXueyan Zhang0Haojie Hao1Li Ma2Yecheng Zhang3Xiao Hu4Zhen Chen5Di Liu6Jianhui Yuan7Zhangli Hu8Wuxiang Guan9Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, ChinaCollege of Life Sciences and Oceanography, Shenzhen University, Shenzhen, ChinaCenter for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, ChinaCenter for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, ChinaCenter for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, ChinaCenter for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, ChinaCenter for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, ChinaNanshan District Center for Disease Control and Prevention, Shenzhen, ChinaCollege of Life Sciences and Oceanography, Shenzhen University, Shenzhen, ChinaCenter for Emerging Infectious Diseases, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, ChinaABSTRACT 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.https://journals.asm.org/doi/10.1128/mBio.01067-21methyltransferase-like 3respiratory syndrome coronavirus-2N6-methyladenosineviral replication |
| spellingShingle | 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 mBio methyltransferase-like 3 respiratory syndrome coronavirus-2 N6-methyladenosine viral replication |
| title | 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_short | 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 |
| topic | methyltransferase-like 3 respiratory syndrome coronavirus-2 N6-methyladenosine viral replication |
| url | https://journals.asm.org/doi/10.1128/mBio.01067-21 |
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