Identification of TMEM53 as a novel SADS-CoV restriction factor that targets viral RNA-dependent RNA polymerase
ABSTRACTZoonotic transmission of coronaviruses (CoVs) poses a serious public health threat. Swine acute diarrhea syndrome coronavirus (SADS-CoV), originating from a bat HKU2-related CoV, causes devastating swine diseases and poses a high risk of spillover to humans. Currently, licensed therapeutics...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Emerging Microbes and Infections |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2023.2249120 |
| _version_ | 1797257047157243904 |
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| author | Yu-Lin Yao Yun Luo Qi Wang Rong Geng Ying Chen Mei-Qin Liu Bei Li Jing Chen Chun-Guang Wu Jing-Kun Jia Jing-Yi Luo Yan-Tong He Ting-Ting Jiang Yan Zhu Ben Hu Peng Zhou Zheng-Li Shi |
| author_facet | Yu-Lin Yao Yun Luo Qi Wang Rong Geng Ying Chen Mei-Qin Liu Bei Li Jing Chen Chun-Guang Wu Jing-Kun Jia Jing-Yi Luo Yan-Tong He Ting-Ting Jiang Yan Zhu Ben Hu Peng Zhou Zheng-Li Shi |
| author_sort | Yu-Lin Yao |
| collection | DOAJ |
| description | ABSTRACTZoonotic transmission of coronaviruses (CoVs) poses a serious public health threat. Swine acute diarrhea syndrome coronavirus (SADS-CoV), originating from a bat HKU2-related CoV, causes devastating swine diseases and poses a high risk of spillover to humans. Currently, licensed therapeutics that can prevent potential human outbreaks are unavailable. Identifying the cellular proteins that restrict viral infection is imperative for developing effective interventions and therapeutics. We utilized a large-scale human cDNA screening and identified transmembrane protein 53 (TMEM53) as a novel cell-intrinsic SADS-CoV restriction factor. The inhibitory effect of TMEM53 on SADS-CoV infection was found to be independent of canonical type I interferon responses. Instead, TMEM53 interacts with non-structural protein 12 (NSP12) and disrupts viral RNA-dependent RNA polymerase (RdRp) complex assembly by interrupting NSP8-NSP12 interaction, thus suppressing viral RdRp activity and RNA synthesis. Deleting the transmembrane domain of TMEM53 resulted in the abrogation of TMEM53-NSP12 interaction and TMEM53 antiviral activity. Importantly, TMEM53 exhibited broad antiviral activity against multiple HKU2-related CoVs. Our findings reveal a novel role of TMEM53 in SADS-CoV restriction and pave the way to host-directed therapeutics against HKU2-related CoV infection. |
| first_indexed | 2024-03-08T11:51:16Z |
| format | Article |
| id | doaj.art-4a79bc04a2ae4817937a82ab1e78f5aa |
| institution | Directory Open Access Journal |
| issn | 2222-1751 |
| language | English |
| last_indexed | 2024-04-24T22:31:25Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj.art-4a79bc04a2ae4817937a82ab1e78f5aa2024-03-19T19:34:17ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512023-12-0112210.1080/22221751.2023.2249120Identification of TMEM53 as a novel SADS-CoV restriction factor that targets viral RNA-dependent RNA polymeraseYu-Lin Yao0Yun Luo1Qi Wang2Rong Geng3Ying Chen4Mei-Qin Liu5Bei Li6Jing Chen7Chun-Guang Wu8Jing-Kun Jia9Jing-Yi Luo10Yan-Tong He11Ting-Ting Jiang12Yan Zhu13Ben Hu14Peng Zhou15Zheng-Li Shi16CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, People’s Republic of ChinaABSTRACTZoonotic transmission of coronaviruses (CoVs) poses a serious public health threat. Swine acute diarrhea syndrome coronavirus (SADS-CoV), originating from a bat HKU2-related CoV, causes devastating swine diseases and poses a high risk of spillover to humans. Currently, licensed therapeutics that can prevent potential human outbreaks are unavailable. Identifying the cellular proteins that restrict viral infection is imperative for developing effective interventions and therapeutics. We utilized a large-scale human cDNA screening and identified transmembrane protein 53 (TMEM53) as a novel cell-intrinsic SADS-CoV restriction factor. The inhibitory effect of TMEM53 on SADS-CoV infection was found to be independent of canonical type I interferon responses. Instead, TMEM53 interacts with non-structural protein 12 (NSP12) and disrupts viral RNA-dependent RNA polymerase (RdRp) complex assembly by interrupting NSP8-NSP12 interaction, thus suppressing viral RdRp activity and RNA synthesis. Deleting the transmembrane domain of TMEM53 resulted in the abrogation of TMEM53-NSP12 interaction and TMEM53 antiviral activity. Importantly, TMEM53 exhibited broad antiviral activity against multiple HKU2-related CoVs. Our findings reveal a novel role of TMEM53 in SADS-CoV restriction and pave the way to host-directed therapeutics against HKU2-related CoV infection.https://www.tandfonline.com/doi/10.1080/22221751.2023.2249120TMEM53SADS-CoVRdRp activityHKU2-related CoVscoronavirus zoonosis |
| spellingShingle | Yu-Lin Yao Yun Luo Qi Wang Rong Geng Ying Chen Mei-Qin Liu Bei Li Jing Chen Chun-Guang Wu Jing-Kun Jia Jing-Yi Luo Yan-Tong He Ting-Ting Jiang Yan Zhu Ben Hu Peng Zhou Zheng-Li Shi Identification of TMEM53 as a novel SADS-CoV restriction factor that targets viral RNA-dependent RNA polymerase Emerging Microbes and Infections TMEM53 SADS-CoV RdRp activity HKU2-related CoVs coronavirus zoonosis |
| title | Identification of TMEM53 as a novel SADS-CoV restriction factor that targets viral RNA-dependent RNA polymerase |
| title_full | Identification of TMEM53 as a novel SADS-CoV restriction factor that targets viral RNA-dependent RNA polymerase |
| title_fullStr | Identification of TMEM53 as a novel SADS-CoV restriction factor that targets viral RNA-dependent RNA polymerase |
| title_full_unstemmed | Identification of TMEM53 as a novel SADS-CoV restriction factor that targets viral RNA-dependent RNA polymerase |
| title_short | Identification of TMEM53 as a novel SADS-CoV restriction factor that targets viral RNA-dependent RNA polymerase |
| title_sort | identification of tmem53 as a novel sads cov restriction factor that targets viral rna dependent rna polymerase |
| topic | TMEM53 SADS-CoV RdRp activity HKU2-related CoVs coronavirus zoonosis |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2023.2249120 |
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