Jingyu Wang, Zhen Wang, Shaobing Wan, Shaotang Ye, Qi Li, Yongbo Liu, Xing Liu, Zihan Chen, Shizhe Liu, Qingmei Xie, Heng Wang, Kun Jia, Shoujun Li
{"title":"结节性皮肤病病毒ORF142通过nbr1介导的STING自噬降解抑制cGAS/STING介导的IFN-I通路","authors":"Jingyu Wang, Zhen Wang, Shaobing Wan, Shaotang Ye, Qi Li, Yongbo Liu, Xing Liu, Zihan Chen, Shizhe Liu, Qingmei Xie, Heng Wang, Kun Jia, Shoujun Li","doi":"10.1016/j.micpath.2025.107959","DOIUrl":null,"url":null,"abstract":"<p><p>Lumpy skin disease (LSD), caused by the Lumpy skin disease virus (LSDV), poses a significant threat to the global cattle farming industry. Viral proteins evolved the ability to escape host immune responses. Here, we demonstrate that LSDV infection inhibits interferon-β (IFN-β) production in Madin-Darby bovine kidney (MDBK) cells, even in the presence of Sendai virus (SEV) inducers. Through further investigation, we identify multiple genes at both ends of the LSDV genome that strongly inhibit IFN-β or NF-κB activation of the promoter. Notably, ORF142 selectively inhibits IFN-β promoter activity but fails to inhibit NF-κB promoter activity. Subsequently, we reveal that ORF142 negatively regulate the cGAS/STING-mediated IFN-I production. Overexpression of ORF142 suppresses IFN-β and interferon-stimulated response element (ISRE) activity, while the absence of ORF142 upregulates the transcription levels of IFN-β and interferon-stimulated genes (ISGs) in MDBK cells. Mechanistically, ORF142 interacts with STING to facilitate autophagy-lysosomal degradation by recruiting NBR1, thereby impeding the activation of downstream signaling molecules, such as IRF3, and inhibiting IFN-I production. In conclusion, our findings elucidate the immune evasion mechanism of ORF142 encoded by LSDV, offering insights for the development of antiviral drugs or attenuated live vaccines to mitigate LSD.</p>","PeriodicalId":18599,"journal":{"name":"Microbial pathogenesis","volume":" ","pages":"107959"},"PeriodicalIF":3.5000,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Lumpy skin disease virus ORF142 suppresses the cGAS/STING-mediated IFN-I pathway through NBR1-mediated STING autophagic degradation.\",\"authors\":\"Jingyu Wang, Zhen Wang, Shaobing Wan, Shaotang Ye, Qi Li, Yongbo Liu, Xing Liu, Zihan Chen, Shizhe Liu, Qingmei Xie, Heng Wang, Kun Jia, Shoujun Li\",\"doi\":\"10.1016/j.micpath.2025.107959\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Lumpy skin disease (LSD), caused by the Lumpy skin disease virus (LSDV), poses a significant threat to the global cattle farming industry. Viral proteins evolved the ability to escape host immune responses. Here, we demonstrate that LSDV infection inhibits interferon-β (IFN-β) production in Madin-Darby bovine kidney (MDBK) cells, even in the presence of Sendai virus (SEV) inducers. Through further investigation, we identify multiple genes at both ends of the LSDV genome that strongly inhibit IFN-β or NF-κB activation of the promoter. Notably, ORF142 selectively inhibits IFN-β promoter activity but fails to inhibit NF-κB promoter activity. Subsequently, we reveal that ORF142 negatively regulate the cGAS/STING-mediated IFN-I production. Overexpression of ORF142 suppresses IFN-β and interferon-stimulated response element (ISRE) activity, while the absence of ORF142 upregulates the transcription levels of IFN-β and interferon-stimulated genes (ISGs) in MDBK cells. Mechanistically, ORF142 interacts with STING to facilitate autophagy-lysosomal degradation by recruiting NBR1, thereby impeding the activation of downstream signaling molecules, such as IRF3, and inhibiting IFN-I production. In conclusion, our findings elucidate the immune evasion mechanism of ORF142 encoded by LSDV, offering insights for the development of antiviral drugs or attenuated live vaccines to mitigate LSD.</p>\",\"PeriodicalId\":18599,\"journal\":{\"name\":\"Microbial pathogenesis\",\"volume\":\" \",\"pages\":\"107959\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Microbial pathogenesis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.micpath.2025.107959\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/8/5 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Microbial pathogenesis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.micpath.2025.107959","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/5 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Lumpy skin disease virus ORF142 suppresses the cGAS/STING-mediated IFN-I pathway through NBR1-mediated STING autophagic degradation.
Lumpy skin disease (LSD), caused by the Lumpy skin disease virus (LSDV), poses a significant threat to the global cattle farming industry. Viral proteins evolved the ability to escape host immune responses. Here, we demonstrate that LSDV infection inhibits interferon-β (IFN-β) production in Madin-Darby bovine kidney (MDBK) cells, even in the presence of Sendai virus (SEV) inducers. Through further investigation, we identify multiple genes at both ends of the LSDV genome that strongly inhibit IFN-β or NF-κB activation of the promoter. Notably, ORF142 selectively inhibits IFN-β promoter activity but fails to inhibit NF-κB promoter activity. Subsequently, we reveal that ORF142 negatively regulate the cGAS/STING-mediated IFN-I production. Overexpression of ORF142 suppresses IFN-β and interferon-stimulated response element (ISRE) activity, while the absence of ORF142 upregulates the transcription levels of IFN-β and interferon-stimulated genes (ISGs) in MDBK cells. Mechanistically, ORF142 interacts with STING to facilitate autophagy-lysosomal degradation by recruiting NBR1, thereby impeding the activation of downstream signaling molecules, such as IRF3, and inhibiting IFN-I production. In conclusion, our findings elucidate the immune evasion mechanism of ORF142 encoded by LSDV, offering insights for the development of antiviral drugs or attenuated live vaccines to mitigate LSD.
期刊介绍:
Microbial Pathogenesis publishes original contributions and reviews about the molecular and cellular mechanisms of infectious diseases. It covers microbiology, host-pathogen interaction and immunology related to infectious agents, including bacteria, fungi, viruses and protozoa. It also accepts papers in the field of clinical microbiology, with the exception of case reports.
Research Areas Include:
-Pathogenesis
-Virulence factors
-Host susceptibility or resistance
-Immune mechanisms
-Identification, cloning and sequencing of relevant genes
-Genetic studies
-Viruses, prokaryotic organisms and protozoa
-Microbiota
-Systems biology related to infectious diseases
-Targets for vaccine design (pre-clinical studies)