NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections
5-Methylcytosine (m5C) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we repor...
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Taylor & Francis Group
2023-12-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2023.2178238 |
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| author | Hongyun Wang Jiangpeng Feng Cong Zeng Jiejie Liu Zhiying Fu Dehe Wang Yafen Wang Lu Zhang Jiali Li Ao Jiang Miao He Yuanyuan Cao Kun Yan Hao Tang Deyin Guo Ke Xu Xiang Zhou Li Zhou Ke Lan Yu Zhou Yu Chen |
| author_facet | Hongyun Wang Jiangpeng Feng Cong Zeng Jiejie Liu Zhiying Fu Dehe Wang Yafen Wang Lu Zhang Jiali Li Ao Jiang Miao He Yuanyuan Cao Kun Yan Hao Tang Deyin Guo Ke Xu Xiang Zhou Li Zhou Ke Lan Yu Zhou Yu Chen |
| author_sort | Hongyun Wang |
| collection | DOAJ |
| description | 5-Methylcytosine (m5C) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we report that NSUN2, a typical m5C methyltransferase, negatively regulates type I interferon responses during various viral infections, including SARS-CoV-2. NSUN2 specifically mediates m5C methylation of IRF3 mRNA and accelerates its degradation, resulting in low levels of IRF3 and downstream IFN-β production. Knockout or knockdown of NSUN2 enhanced type I interferon and downstream ISGs during various viral infection in vitro. And in vivo, the antiviral innate response is more dramatically enhanced in Nsun2+/− mice than in Nsun2+/+ mice. The highly m5C methylated cytosines in IRF3 mRNA were identified, and their mutation enhanced cellular IRF3 mRNA levels. Moreover, infection with Sendai virus (SeV), vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), or Zika virus (ZIKV) resulted in a reduction of endogenous NSUN2 levels. Especially, SARS-CoV-2 infection (WT strain and BA.1 omicron variant) also decreased endogenous levels of NSUN2 in COVID-19 patients and K18-hACE2 KI mice, further increasing type I interferon and downstream ISGs. Together, our findings reveal that NSUN2 serves as a negative regulator of interferon response by accelerating the fast turnover of IRF3 mRNA, while endogenous NSUN2 levels decrease during SARS-CoV-2 and various viral infections to boost antiviral responses for effective elimination of viruses. |
| format | Article |
| id | doaj-art-c0168b5f00514f569e9aed0a3de13fa0 |
| institution | OA Journals |
| issn | 2222-1751 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj-art-c0168b5f00514f569e9aed0a3de13fa02025-08-20T01:49:50ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512023-12-0112110.1080/22221751.2023.2178238NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infectionsHongyun Wang0Jiangpeng Feng1Cong Zeng2Jiejie Liu3Zhiying Fu4Dehe Wang5Yafen Wang6Lu Zhang7Jiali Li8Ao Jiang9Miao He10Yuanyuan Cao11Kun Yan12Hao Tang13Deyin Guo14Ke Xu15Xiang Zhou16Li Zhou17Ke Lan18Yu Zhou19Yu Chen20State Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaCollege of Chemistry and Molecular Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaSchool of Medicine, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaDepartment of Microbiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaHeart Center of Henan Provincial People’s Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaSchool of Medicine, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaCollege of Chemistry and Molecular Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of ChinaState Key Laboratory of Virology, RNA Institute, College of Life Sciences, Wuhan University, Wuhan, People’s Republic of China5-Methylcytosine (m5C) is a widespread post-transcriptional RNA modification and is reported to be involved in manifold cellular responses and biological processes through regulating RNA metabolism. However, its regulatory role in antiviral innate immunity has not yet been elucidated. Here, we report that NSUN2, a typical m5C methyltransferase, negatively regulates type I interferon responses during various viral infections, including SARS-CoV-2. NSUN2 specifically mediates m5C methylation of IRF3 mRNA and accelerates its degradation, resulting in low levels of IRF3 and downstream IFN-β production. Knockout or knockdown of NSUN2 enhanced type I interferon and downstream ISGs during various viral infection in vitro. And in vivo, the antiviral innate response is more dramatically enhanced in Nsun2+/− mice than in Nsun2+/+ mice. The highly m5C methylated cytosines in IRF3 mRNA were identified, and their mutation enhanced cellular IRF3 mRNA levels. Moreover, infection with Sendai virus (SeV), vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), or Zika virus (ZIKV) resulted in a reduction of endogenous NSUN2 levels. Especially, SARS-CoV-2 infection (WT strain and BA.1 omicron variant) also decreased endogenous levels of NSUN2 in COVID-19 patients and K18-hACE2 KI mice, further increasing type I interferon and downstream ISGs. Together, our findings reveal that NSUN2 serves as a negative regulator of interferon response by accelerating the fast turnover of IRF3 mRNA, while endogenous NSUN2 levels decrease during SARS-CoV-2 and various viral infections to boost antiviral responses for effective elimination of viruses.https://www.tandfonline.com/doi/10.1080/22221751.2023.21782385-methylcytosineRNA methyltransferaseviral infectionsantiviral innate immunitySARS-CoV-2 |
| spellingShingle | Hongyun Wang Jiangpeng Feng Cong Zeng Jiejie Liu Zhiying Fu Dehe Wang Yafen Wang Lu Zhang Jiali Li Ao Jiang Miao He Yuanyuan Cao Kun Yan Hao Tang Deyin Guo Ke Xu Xiang Zhou Li Zhou Ke Lan Yu Zhou Yu Chen NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections Emerging Microbes and Infections 5-methylcytosine RNA methyltransferase viral infections antiviral innate immunity SARS-CoV-2 |
| title | NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections |
| title_full | NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections |
| title_fullStr | NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections |
| title_full_unstemmed | NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections |
| title_short | NSUN2-mediated m5C methylation of IRF3 mRNA negatively regulates type I interferon responses during various viral infections |
| title_sort | nsun2 mediated m5c methylation of irf3 mrna negatively regulates type i interferon responses during various viral infections |
| topic | 5-methylcytosine RNA methyltransferase viral infections antiviral innate immunity SARS-CoV-2 |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2023.2178238 |
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