The nuclear localization signal of monkeypox virus protein P2 orthologue is critical for inhibition of IRF3-mediated innate immunity
The Orthopoxvirus (OPXV) genus of the Poxviridae includes human pathogens variola virus (VARV), monkeypox virus (MPXV), vaccinia virus (VACV), and a number of zoonotic viruses. A number of Bcl-2-like proteins of VACV are involved in escaping the host innate immunity. However, little work has been de...
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Taylor & Francis Group
2024-12-01
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| Series: | Emerging Microbes and Infections |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2024.2372344 |
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| author | Pengtao Jiao Jianing Ma Yuna Zhao Xiaoxiao Jia Haoran Zhang Wenhui Fan Xiaojuan Jia Xiaoyuan Bai Yiqi Zhao Yongxu Lu He Zhang Jiayin Guo Gang Pang Ke Zhang Min Fang Minghua Li Wenjun Liu Geoffrey L. Smith Lei Sun |
| author_facet | Pengtao Jiao Jianing Ma Yuna Zhao Xiaoxiao Jia Haoran Zhang Wenhui Fan Xiaojuan Jia Xiaoyuan Bai Yiqi Zhao Yongxu Lu He Zhang Jiayin Guo Gang Pang Ke Zhang Min Fang Minghua Li Wenjun Liu Geoffrey L. Smith Lei Sun |
| author_sort | Pengtao Jiao |
| collection | DOAJ |
| description | The Orthopoxvirus (OPXV) genus of the Poxviridae includes human pathogens variola virus (VARV), monkeypox virus (MPXV), vaccinia virus (VACV), and a number of zoonotic viruses. A number of Bcl-2-like proteins of VACV are involved in escaping the host innate immunity. However, little work has been devoted to the evolution and function of their orthologues in other OPXVs. Here, we found that MPXV protein P2, encoded by the P2L gene, and P2 orthologues from other OPXVs, such as VACV protein N2, localize to the nucleus and antagonize interferon (IFN) production. Exceptions to this were the truncated P2 orthologues in camelpox virus (CMLV) and taterapox virus (TATV) that lacked the nuclear localization signal (NLS). Mechanistically, the NLS of MPXV P2 interacted with karyopherin α-2 (KPNA2) to facilitate P2 nuclear translocation, and competitively inhibited KPNA2-mediated IRF3 nuclear translocation and downstream IFN production. Deletion of the NLS in P2 or orthologues significantly enhanced IRF3 nuclear translocation and innate immune responses, thereby reducing viral replication. Moreover, deletion of NLS from N2 in VACV attenuated viral replication and virulence in mice. These data demonstrate that the NLS-mediated translocation of P2 is critical for P2-induced inhibition of innate immunity. Our findings contribute to an in-depth understanding of the mechanisms of OPXV P2 orthologue in innate immune evasion. |
| format | Article |
| id | doaj-art-e39d1e875dcf4cadb8064dd29db4dc45 |
| institution | Kabale University |
| issn | 2222-1751 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj-art-e39d1e875dcf4cadb8064dd29db4dc452024-12-07T04:40:18ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512024-12-0113110.1080/22221751.2024.2372344The nuclear localization signal of monkeypox virus protein P2 orthologue is critical for inhibition of IRF3-mediated innate immunityPengtao Jiao0Jianing Ma1Yuna Zhao2Xiaoxiao Jia3Haoran Zhang4Wenhui Fan5Xiaojuan Jia6Xiaoyuan Bai7Yiqi Zhao8Yongxu Lu9He Zhang10Jiayin Guo11Gang Pang12Ke Zhang13Min Fang14Minghua Li15Wenjun Liu16Geoffrey L. Smith17Lei Sun18CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaSir William Dunn School of Pathology, University of Oxford, Oxford, UKSir William Dunn School of Pathology, University of Oxford, Oxford, UKInstitute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, People’s Republic of ChinaShanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, People’s Republic of ChinaShanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, People’s Republic of ChinaShanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, People’s Republic of ChinaSchool of Life Sciences, Henan University, Kaifeng, People’s Republic of ChinaKunming National High-level Biosafety Research Center for Non-Human Primates, Center for Biosafety Mega-Science, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, People’s Republic of ChinaCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaSir William Dunn School of Pathology, University of Oxford, Oxford, UKCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, People’s Republic of ChinaThe Orthopoxvirus (OPXV) genus of the Poxviridae includes human pathogens variola virus (VARV), monkeypox virus (MPXV), vaccinia virus (VACV), and a number of zoonotic viruses. A number of Bcl-2-like proteins of VACV are involved in escaping the host innate immunity. However, little work has been devoted to the evolution and function of their orthologues in other OPXVs. Here, we found that MPXV protein P2, encoded by the P2L gene, and P2 orthologues from other OPXVs, such as VACV protein N2, localize to the nucleus and antagonize interferon (IFN) production. Exceptions to this were the truncated P2 orthologues in camelpox virus (CMLV) and taterapox virus (TATV) that lacked the nuclear localization signal (NLS). Mechanistically, the NLS of MPXV P2 interacted with karyopherin α-2 (KPNA2) to facilitate P2 nuclear translocation, and competitively inhibited KPNA2-mediated IRF3 nuclear translocation and downstream IFN production. Deletion of the NLS in P2 or orthologues significantly enhanced IRF3 nuclear translocation and innate immune responses, thereby reducing viral replication. Moreover, deletion of NLS from N2 in VACV attenuated viral replication and virulence in mice. These data demonstrate that the NLS-mediated translocation of P2 is critical for P2-induced inhibition of innate immunity. Our findings contribute to an in-depth understanding of the mechanisms of OPXV P2 orthologue in innate immune evasion.https://www.tandfonline.com/doi/10.1080/22221751.2024.2372344Orthopoxvirusmonkeypox virusIRF3innate immunityimmune evasion |
| spellingShingle | Pengtao Jiao Jianing Ma Yuna Zhao Xiaoxiao Jia Haoran Zhang Wenhui Fan Xiaojuan Jia Xiaoyuan Bai Yiqi Zhao Yongxu Lu He Zhang Jiayin Guo Gang Pang Ke Zhang Min Fang Minghua Li Wenjun Liu Geoffrey L. Smith Lei Sun The nuclear localization signal of monkeypox virus protein P2 orthologue is critical for inhibition of IRF3-mediated innate immunity Emerging Microbes and Infections Orthopoxvirus monkeypox virus IRF3 innate immunity immune evasion |
| title | The nuclear localization signal of monkeypox virus protein P2 orthologue is critical for inhibition of IRF3-mediated innate immunity |
| title_full | The nuclear localization signal of monkeypox virus protein P2 orthologue is critical for inhibition of IRF3-mediated innate immunity |
| title_fullStr | The nuclear localization signal of monkeypox virus protein P2 orthologue is critical for inhibition of IRF3-mediated innate immunity |
| title_full_unstemmed | The nuclear localization signal of monkeypox virus protein P2 orthologue is critical for inhibition of IRF3-mediated innate immunity |
| title_short | The nuclear localization signal of monkeypox virus protein P2 orthologue is critical for inhibition of IRF3-mediated innate immunity |
| title_sort | nuclear localization signal of monkeypox virus protein p2 orthologue is critical for inhibition of irf3 mediated innate immunity |
| topic | Orthopoxvirus monkeypox virus IRF3 innate immunity immune evasion |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2024.2372344 |
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