Viruses hijack FPN1 to disrupt iron withholding and suppress host defense
Abstract Viruses rely on intracellular materials, including iron, to complete their life cycles and iron withholding may limit viral infections. However, the mechanisms through which viruses disrupt host iron homeostasis and the impact of intracellular iron on the host’s antiviral defense aren’t wel...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60031-w |
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| author | Li Tong Jie Wang Yunjin Ma Chunying Wang Yue Fu Qi Li Chengjiang Gao Hui Song Ying Qin Chunyuan Zhao Wei Zhao |
| author_facet | Li Tong Jie Wang Yunjin Ma Chunying Wang Yue Fu Qi Li Chengjiang Gao Hui Song Ying Qin Chunyuan Zhao Wei Zhao |
| author_sort | Li Tong |
| collection | DOAJ |
| description | Abstract Viruses rely on intracellular materials, including iron, to complete their life cycles and iron withholding may limit viral infections. However, the mechanisms through which viruses disrupt host iron homeostasis and the impact of intracellular iron on the host’s antiviral defense aren’t well studied. Here we show that viral infections facilitate the polyubiquitination and degradation of ferroportin (FPN1, the only cellular iron exporter) by upregulating the host E3 ubiquitin ligase DTX3L, leading to an elevation in cellular iron levels. Excessive ferrous iron suppresses type I IFN responses and autophagy by promoting TBK1 hydroxylation and STING carbonylation in macrophages. FPN1 deficiency suppresses host antiviral defense and facilitates viral replication in vitro and in vivo, while DTX3L deficiency has the opposite effect. These results reveal that viruses hijack host FPN1 to disrupt iron withholding and achieve immune escape, and suggest that iron homeostasis maintained by FPN1 is required for the optimal activation of TBK1- and STING-dependent antiviral responses. |
| format | Article |
| id | doaj-art-44894202bf0f4dc091b8498ceec932da |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-44894202bf0f4dc091b8498ceec932da2025-08-20T03:03:37ZengNature PortfolioNature Communications2041-17232025-07-0116111410.1038/s41467-025-60031-wViruses hijack FPN1 to disrupt iron withholding and suppress host defenseLi Tong0Jie Wang1Yunjin Ma2Chunying Wang3Yue Fu4Qi Li5Chengjiang Gao6Hui Song7Ying Qin8Chunyuan Zhao9Wei Zhao10Department of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityDepartment of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityDepartment of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityDepartment of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityDepartment of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityDepartment of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityDepartment of Immunology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityDepartment of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityDepartment of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityDepartment of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityDepartment of Pathogenic Biology, Key Laboratory of Infection and Immunity of Shandong Province, and Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Basic Medical Science, Cheeloo College of Medicine, Shandong UniversityAbstract Viruses rely on intracellular materials, including iron, to complete their life cycles and iron withholding may limit viral infections. However, the mechanisms through which viruses disrupt host iron homeostasis and the impact of intracellular iron on the host’s antiviral defense aren’t well studied. Here we show that viral infections facilitate the polyubiquitination and degradation of ferroportin (FPN1, the only cellular iron exporter) by upregulating the host E3 ubiquitin ligase DTX3L, leading to an elevation in cellular iron levels. Excessive ferrous iron suppresses type I IFN responses and autophagy by promoting TBK1 hydroxylation and STING carbonylation in macrophages. FPN1 deficiency suppresses host antiviral defense and facilitates viral replication in vitro and in vivo, while DTX3L deficiency has the opposite effect. These results reveal that viruses hijack host FPN1 to disrupt iron withholding and achieve immune escape, and suggest that iron homeostasis maintained by FPN1 is required for the optimal activation of TBK1- and STING-dependent antiviral responses.https://doi.org/10.1038/s41467-025-60031-w |
| spellingShingle | Li Tong Jie Wang Yunjin Ma Chunying Wang Yue Fu Qi Li Chengjiang Gao Hui Song Ying Qin Chunyuan Zhao Wei Zhao Viruses hijack FPN1 to disrupt iron withholding and suppress host defense Nature Communications |
| title | Viruses hijack FPN1 to disrupt iron withholding and suppress host defense |
| title_full | Viruses hijack FPN1 to disrupt iron withholding and suppress host defense |
| title_fullStr | Viruses hijack FPN1 to disrupt iron withholding and suppress host defense |
| title_full_unstemmed | Viruses hijack FPN1 to disrupt iron withholding and suppress host defense |
| title_short | Viruses hijack FPN1 to disrupt iron withholding and suppress host defense |
| title_sort | viruses hijack fpn1 to disrupt iron withholding and suppress host defense |
| url | https://doi.org/10.1038/s41467-025-60031-w |
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