African swine fever virus MGF505-4R facilitates cGAS degradation through TOLLIP-mediated selective autophagy and inhibits the formation of ISGF3 to evade innate immunity
Abstract African swine fever virus (ASFV) causes acute and highly lethal disease in pigs. To counteract host defense systems and facilitate virus infection, many ASFV-encoded proteins have regulatory effects on the innate immune response. In this study, we constructed an MGF505-4R-deleted ASFV strai...
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BMC
2025-07-01
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| Series: | Veterinary Research |
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| Online Access: | https://doi.org/10.1186/s13567-025-01569-x |
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| author | Manman Yao Pengfei Li Xiangmin Li Wentao Li Ping Qian |
| author_facet | Manman Yao Pengfei Li Xiangmin Li Wentao Li Ping Qian |
| author_sort | Manman Yao |
| collection | DOAJ |
| description | Abstract African swine fever virus (ASFV) causes acute and highly lethal disease in pigs. To counteract host defense systems and facilitate virus infection, many ASFV-encoded proteins have regulatory effects on the innate immune response. In this study, we constructed an MGF505-4R-deleted ASFV strain (ASFV-Δ4R) and found that, compared with the wild-type ASFV, ASFV-Δ4R infection significantly increased IFN-β production and elevated the mRNA levels of antiviral genes in porcine alveolar macrophages. Mechanistically, MGF505-4R interacts with cGAS and promotes its degradation by triggering Toll-interacting protein (TOLLIP)-mediated selective autophagy. Specifically, MGF505-4R enhanced the interaction between cGAS and TOLLIP, which subsequently led to increased degradation of cGAS. Additionally, MGF505-4R inhibited IFN-β-induced signal transmission by interacting with STAT1 and STAT2 and impeding their phosphorylation. This effect consequently prevented the formation of the ISGF3 heterotrimer and its subsequent translocation to the nucleus, leading to the downregulation of antiviral genes. As expected, compared with the ASFV-WT strain, ASFV-Δ4R infection increased phosphorylation of STAT1 and STAT2 and subsequent ISGF3 formation, leading to an elevated expression of antiviral gene ISGs. This discovery enhances the understanding of the immune regulation strategies evolved by ASFV and offers valuable perspectives for antiviral research targeting ASFV. |
| format | Article |
| id | doaj-art-3f7d09ddc9ab48f082debc5fcab1bad0 |
| institution | Kabale University |
| issn | 1297-9716 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| spelling | doaj-art-3f7d09ddc9ab48f082debc5fcab1bad02025-08-20T03:37:40ZengBMCVeterinary Research1297-97162025-07-0156111910.1186/s13567-025-01569-xAfrican swine fever virus MGF505-4R facilitates cGAS degradation through TOLLIP-mediated selective autophagy and inhibits the formation of ISGF3 to evade innate immunityManman Yao0Pengfei Li1Xiangmin Li2Wentao Li3Ping Qian4National Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityAbstract African swine fever virus (ASFV) causes acute and highly lethal disease in pigs. To counteract host defense systems and facilitate virus infection, many ASFV-encoded proteins have regulatory effects on the innate immune response. In this study, we constructed an MGF505-4R-deleted ASFV strain (ASFV-Δ4R) and found that, compared with the wild-type ASFV, ASFV-Δ4R infection significantly increased IFN-β production and elevated the mRNA levels of antiviral genes in porcine alveolar macrophages. Mechanistically, MGF505-4R interacts with cGAS and promotes its degradation by triggering Toll-interacting protein (TOLLIP)-mediated selective autophagy. Specifically, MGF505-4R enhanced the interaction between cGAS and TOLLIP, which subsequently led to increased degradation of cGAS. Additionally, MGF505-4R inhibited IFN-β-induced signal transmission by interacting with STAT1 and STAT2 and impeding their phosphorylation. This effect consequently prevented the formation of the ISGF3 heterotrimer and its subsequent translocation to the nucleus, leading to the downregulation of antiviral genes. As expected, compared with the ASFV-WT strain, ASFV-Δ4R infection increased phosphorylation of STAT1 and STAT2 and subsequent ISGF3 formation, leading to an elevated expression of antiviral gene ISGs. This discovery enhances the understanding of the immune regulation strategies evolved by ASFV and offers valuable perspectives for antiviral research targeting ASFV.https://doi.org/10.1186/s13567-025-01569-xASFVMGF505-4RdegradationautolysosomecGAS-STINGimmune evasion |
| spellingShingle | Manman Yao Pengfei Li Xiangmin Li Wentao Li Ping Qian African swine fever virus MGF505-4R facilitates cGAS degradation through TOLLIP-mediated selective autophagy and inhibits the formation of ISGF3 to evade innate immunity Veterinary Research ASFV MGF505-4R degradation autolysosome cGAS-STING immune evasion |
| title | African swine fever virus MGF505-4R facilitates cGAS degradation through TOLLIP-mediated selective autophagy and inhibits the formation of ISGF3 to evade innate immunity |
| title_full | African swine fever virus MGF505-4R facilitates cGAS degradation through TOLLIP-mediated selective autophagy and inhibits the formation of ISGF3 to evade innate immunity |
| title_fullStr | African swine fever virus MGF505-4R facilitates cGAS degradation through TOLLIP-mediated selective autophagy and inhibits the formation of ISGF3 to evade innate immunity |
| title_full_unstemmed | African swine fever virus MGF505-4R facilitates cGAS degradation through TOLLIP-mediated selective autophagy and inhibits the formation of ISGF3 to evade innate immunity |
| title_short | African swine fever virus MGF505-4R facilitates cGAS degradation through TOLLIP-mediated selective autophagy and inhibits the formation of ISGF3 to evade innate immunity |
| title_sort | african swine fever virus mgf505 4r facilitates cgas degradation through tollip mediated selective autophagy and inhibits the formation of isgf3 to evade innate immunity |
| topic | ASFV MGF505-4R degradation autolysosome cGAS-STING immune evasion |
| url | https://doi.org/10.1186/s13567-025-01569-x |
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