PWWP3A disrupts the assembly of VISA/MAVS signalosome to inhibit innate immune response against RNA viruses
Abstract VISA/MAVS is crucial in antiviral innate immunity. Upon RNA virus infection, VISA recruits TBK1 via TRAFs to mitochondria, inducing IRF3 phosphorylation and type I interferons. However, TBK1 recruitment mechanisms via individual TRAFs are unclear. Here, we reveal that PWWP domain-containing...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59421-x |
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| author | Mengling Shi Cong Wang Zhen Chen Yidan Zhou Liang Yue Yu Liu Tiannan Guo Jun Shang Haotian Xu Yu Zhang Mengcheng Luo Caoqi Lei |
| author_facet | Mengling Shi Cong Wang Zhen Chen Yidan Zhou Liang Yue Yu Liu Tiannan Guo Jun Shang Haotian Xu Yu Zhang Mengcheng Luo Caoqi Lei |
| author_sort | Mengling Shi |
| collection | DOAJ |
| description | Abstract VISA/MAVS is crucial in antiviral innate immunity. Upon RNA virus infection, VISA recruits TBK1 via TRAFs to mitochondria, inducing IRF3 phosphorylation and type I interferons. However, TBK1 recruitment mechanisms via individual TRAFs are unclear. Here, we reveal that PWWP domain-containing 3A (PWWP3A) serves as a negative regulator of RNA virus-triggered signaling. During viral infection, PWWP3A translocates from nucleus to the mitochondria, competing with TRAF6 for binding to VISA, thereby impeding the recruitment of TBK1 and inhibiting IRF3 activation. However, the extent of PWWP3A-mediated inhibition is regulated by the E3 ligase PJA2, which induces PWWP3A degradation post-infection, highlighting the intricate regulatory network in antiviral immunity. Consistently, PWWP3A deficiency enhances antiviral responses, and Pwwp3a −/− mice exhibit elevated levels of type I interferons and displayed greater resistance following RNA virus infection. Together, our findings unveil the inhibitory role of PWWP3A in virus-triggered signaling, which provides insights into preventing excessive immune responses. |
| format | Article |
| id | doaj-art-7f5f8371e7ff4c8fbc089925788b6c2a |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7f5f8371e7ff4c8fbc089925788b6c2a2025-08-20T01:47:29ZengNature PortfolioNature Communications2041-17232025-05-0116111510.1038/s41467-025-59421-xPWWP3A disrupts the assembly of VISA/MAVS signalosome to inhibit innate immune response against RNA virusesMengling Shi0Cong Wang1Zhen Chen2Yidan Zhou3Liang Yue4Yu Liu5Tiannan Guo6Jun Shang7Haotian Xu8Yu Zhang9Mengcheng Luo10Caoqi Lei11State Key Laboratory of Virology and Biosafety, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan UniversityState Key Laboratory of Virology and Biosafety, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan UniversityState Key Laboratory of Virology and Biosafety, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan UniversityDepartment of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan UniversityCenter for Intelligent Proteomics, Westlake Laboratory of Life Sciences and BiomedicineState Key Laboratory of Virology and Biosafety, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan UniversityCenter for Intelligent Proteomics, Westlake Laboratory of Life Sciences and BiomedicineSpecAlly Life Technology Co. Ltd.State Key Laboratory of Virology and Biosafety, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan UniversitySchool of Basic Medical Sciences, Lanzhou UniversityHubei Provincial Key Laboratory of Developmentally Originated Disease, TaiKang Center for Life and Medical Sciences, School of Basic Medical Sciences, Wuhan UniversityState Key Laboratory of Virology and Biosafety, College of Life Sciences, Frontier Science Center for Immunology and Metabolism, Wuhan UniversityAbstract VISA/MAVS is crucial in antiviral innate immunity. Upon RNA virus infection, VISA recruits TBK1 via TRAFs to mitochondria, inducing IRF3 phosphorylation and type I interferons. However, TBK1 recruitment mechanisms via individual TRAFs are unclear. Here, we reveal that PWWP domain-containing 3A (PWWP3A) serves as a negative regulator of RNA virus-triggered signaling. During viral infection, PWWP3A translocates from nucleus to the mitochondria, competing with TRAF6 for binding to VISA, thereby impeding the recruitment of TBK1 and inhibiting IRF3 activation. However, the extent of PWWP3A-mediated inhibition is regulated by the E3 ligase PJA2, which induces PWWP3A degradation post-infection, highlighting the intricate regulatory network in antiviral immunity. Consistently, PWWP3A deficiency enhances antiviral responses, and Pwwp3a −/− mice exhibit elevated levels of type I interferons and displayed greater resistance following RNA virus infection. Together, our findings unveil the inhibitory role of PWWP3A in virus-triggered signaling, which provides insights into preventing excessive immune responses.https://doi.org/10.1038/s41467-025-59421-x |
| spellingShingle | Mengling Shi Cong Wang Zhen Chen Yidan Zhou Liang Yue Yu Liu Tiannan Guo Jun Shang Haotian Xu Yu Zhang Mengcheng Luo Caoqi Lei PWWP3A disrupts the assembly of VISA/MAVS signalosome to inhibit innate immune response against RNA viruses Nature Communications |
| title | PWWP3A disrupts the assembly of VISA/MAVS signalosome to inhibit innate immune response against RNA viruses |
| title_full | PWWP3A disrupts the assembly of VISA/MAVS signalosome to inhibit innate immune response against RNA viruses |
| title_fullStr | PWWP3A disrupts the assembly of VISA/MAVS signalosome to inhibit innate immune response against RNA viruses |
| title_full_unstemmed | PWWP3A disrupts the assembly of VISA/MAVS signalosome to inhibit innate immune response against RNA viruses |
| title_short | PWWP3A disrupts the assembly of VISA/MAVS signalosome to inhibit innate immune response against RNA viruses |
| title_sort | pwwp3a disrupts the assembly of visa mavs signalosome to inhibit innate immune response against rna viruses |
| url | https://doi.org/10.1038/s41467-025-59421-x |
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