Human papillomavirus E1 proteins inhibit RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT signaling pathways to evade innate antiviral immunity
Human papillomavirus (HPV) is a major etiological agent of both malignant and benign lesions, with high-risk types, such as HPV16 and HPV18, being strongly linked to cervical cancer, while low-risk types like HPV11 are associated with benign conditions. While viral proteins such as E6 and E7 are wel...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1549766/full |
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| author | Jin-Xin Li Jing Zhang Cheng-Hao Li Yun-Fang Li Hui-Min Chen Tao Li Qing Zhang Qing Zhang Bei-Hua Kong Bei-Hua Kong Pei-Hui Wang Pei-Hui Wang |
| author_facet | Jin-Xin Li Jing Zhang Cheng-Hao Li Yun-Fang Li Hui-Min Chen Tao Li Qing Zhang Qing Zhang Bei-Hua Kong Bei-Hua Kong Pei-Hui Wang Pei-Hui Wang |
| author_sort | Jin-Xin Li |
| collection | DOAJ |
| description | Human papillomavirus (HPV) is a major etiological agent of both malignant and benign lesions, with high-risk types, such as HPV16 and HPV18, being strongly linked to cervical cancer, while low-risk types like HPV11 are associated with benign conditions. While viral proteins such as E6 and E7 are well-established regulators of immune evasion, the role of E1 in modulating the host antiviral responses remains insufficiently characterized. This study investigates the immunomodulatory functions of HPV16 and HPV11 E1 in suppressing innate antiviral immune signaling pathways. Through a combination of RT-qPCR and luciferase reporter assays, we demonstrate that E1 suppresses the production of interferons and interferon-stimulated genes triggered by viral infections and the activation of RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT pathways. Co-immunoprecipitation assays reveal that E1 interacts directly with key signaling molecules within these pathways. E1 also impairs TBK1 and IRF3 phosphorylation and obstructs the nuclear translocation of IRF3, thereby broadly suppressing IFN responses. Additionally, E1 disrupts the JAK-STAT pathway by binding STAT1, which prevents the assembly and nuclear localization of the ISGF3 complex containing STAT1, STAT2, and IRF9, thereby further diminishing antiviral response. These findings establish E1 as a pivotal regulator of immune evasion and suggest its potential as a novel therapeutic target to enhance antiviral immunity in HPV-associated diseases. |
| format | Article |
| id | doaj-art-a5c7db1a5ee44a11b84c907087a044c5 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-a5c7db1a5ee44a11b84c907087a044c52025-08-20T02:24:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-04-011610.3389/fimmu.2025.15497661549766Human papillomavirus E1 proteins inhibit RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT signaling pathways to evade innate antiviral immunityJin-Xin Li0Jing Zhang1Cheng-Hao Li2Yun-Fang Li3Hui-Min Chen4Tao Li5Qing Zhang6Qing Zhang7Bei-Hua Kong8Bei-Hua Kong9Pei-Hui Wang10Pei-Hui Wang11Department of Infectious Disease and Hepatology, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Infectious Disease and Hepatology, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Infectious Disease and Hepatology, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaDepartment of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, ChinaGynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, ChinaGynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, Jinan, ChinaDepartment of Infectious Disease and Hepatology, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaKey Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, ChinaHuman papillomavirus (HPV) is a major etiological agent of both malignant and benign lesions, with high-risk types, such as HPV16 and HPV18, being strongly linked to cervical cancer, while low-risk types like HPV11 are associated with benign conditions. While viral proteins such as E6 and E7 are well-established regulators of immune evasion, the role of E1 in modulating the host antiviral responses remains insufficiently characterized. This study investigates the immunomodulatory functions of HPV16 and HPV11 E1 in suppressing innate antiviral immune signaling pathways. Through a combination of RT-qPCR and luciferase reporter assays, we demonstrate that E1 suppresses the production of interferons and interferon-stimulated genes triggered by viral infections and the activation of RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT pathways. Co-immunoprecipitation assays reveal that E1 interacts directly with key signaling molecules within these pathways. E1 also impairs TBK1 and IRF3 phosphorylation and obstructs the nuclear translocation of IRF3, thereby broadly suppressing IFN responses. Additionally, E1 disrupts the JAK-STAT pathway by binding STAT1, which prevents the assembly and nuclear localization of the ISGF3 complex containing STAT1, STAT2, and IRF9, thereby further diminishing antiviral response. These findings establish E1 as a pivotal regulator of immune evasion and suggest its potential as a novel therapeutic target to enhance antiviral immunity in HPV-associated diseases.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1549766/fullHPV E1innate immunityRIG-I/MDA5-MAVScGAS-STINGJAK-STATimmune evasion |
| spellingShingle | Jin-Xin Li Jing Zhang Cheng-Hao Li Yun-Fang Li Hui-Min Chen Tao Li Qing Zhang Qing Zhang Bei-Hua Kong Bei-Hua Kong Pei-Hui Wang Pei-Hui Wang Human papillomavirus E1 proteins inhibit RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT signaling pathways to evade innate antiviral immunity Frontiers in Immunology HPV E1 innate immunity RIG-I/MDA5-MAVS cGAS-STING JAK-STAT immune evasion |
| title | Human papillomavirus E1 proteins inhibit RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT signaling pathways to evade innate antiviral immunity |
| title_full | Human papillomavirus E1 proteins inhibit RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT signaling pathways to evade innate antiviral immunity |
| title_fullStr | Human papillomavirus E1 proteins inhibit RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT signaling pathways to evade innate antiviral immunity |
| title_full_unstemmed | Human papillomavirus E1 proteins inhibit RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT signaling pathways to evade innate antiviral immunity |
| title_short | Human papillomavirus E1 proteins inhibit RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT signaling pathways to evade innate antiviral immunity |
| title_sort | human papillomavirus e1 proteins inhibit rig i mda5 mavs tlr3 trif cgas sting and jak stat signaling pathways to evade innate antiviral immunity |
| topic | HPV E1 innate immunity RIG-I/MDA5-MAVS cGAS-STING JAK-STAT immune evasion |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1549766/full |
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