Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon
ABSTRACT Nuclear cyclic GMP-AMP synthetase (cGAS) binds to nucleosome with high affinity to prevent its activation by self-DNA. Upon stimulation with double-stranded DNA, cGAS is activated and translocates from the nucleus to the cytoplasm, guided by its N-terminal domain. However, it remains unclea...
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American Society for Microbiology
2025-04-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03395-24 |
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| author | Lei Wu Ya Yan Ye Yuan Zhenchao Zhao Weiyu Qu Xiangyu Huang Haiwei Wang Pingwei Li Xin Li |
| author_facet | Lei Wu Ya Yan Ye Yuan Zhenchao Zhao Weiyu Qu Xiangyu Huang Haiwei Wang Pingwei Li Xin Li |
| author_sort | Lei Wu |
| collection | DOAJ |
| description | ABSTRACT Nuclear cyclic GMP-AMP synthetase (cGAS) binds to nucleosome with high affinity to prevent its activation by self-DNA. Upon stimulation with double-stranded DNA, cGAS is activated and translocates from the nucleus to the cytoplasm, guided by its N-terminal domain. However, it remains unclear whether viruses can hijack cGAS translocation and regulate its activation. Here, we discovered that the protease 3C of picornavirus Seneca Valley virus (SVV) translocates from the cytoplasm to the nucleus upon viral infection and binds to nuclear DNA. Protease 3C specifically cleaves histone H2A while leaving other histone proteins unaffected. Additionally, DNA binding enhances the protease 3C’s ability to cleave nuclear cGAS, leading to its retention in the nucleus. This, in turn, suppresses the induction of type I interferon (IFN-I) following poly(dA:dT) stimulation. These findings reveal a novel mechanism by which a viral protease binds nuclear DNA, cleaves nuclear cGAS and histone H2A, and thereby mislocalizes cGAS, facilitating immune evasion.IMPORTANCECyclic GMP-AMP synthetase (cGAS) is robustly expressed in the nucleus and tightly tethered by chromatin to prevent its activation with self-DNA. During stimulation or infection, nuclear cGAS is activated and translocates from the nucleus to the cytoplasm. However, the viral strategies specifically targeting nuclear cGAS are completely unexplored. Here, we discovered that protease 3C of Seneca Valley virus translocates from the cytoplasm to the nucleus upon viral infection, binds to nuclear DNA, and specifically cleaves H2A. Furthermore, DNA binding to 3C enhances the cleavage of nuclear cGAS within its N-terminal domain. The hindrance of cGAS translocation from the nucleus to the cytoplasm results in the suppression of IFN-I induction and leads to immune evasion. This work uncovers a unique mechanism wherein a viral protease binds to nuclear DNA and cleaves nuclear cGAS and histone H2A, leading to viral evasion of cGAS-mediated immune restriction. |
| format | Article |
| id | doaj-art-3ea11ccdec3f45d6989d85c9c86793f6 |
| institution | OA Journals |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-3ea11ccdec3f45d6989d85c9c86793f62025-08-20T02:07:59ZengAmerican Society for MicrobiologymBio2150-75112025-04-0116410.1128/mbio.03395-24Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferonLei Wu0Ya Yan1Ye Yuan2Zhenchao Zhao3Weiyu Qu4Xiangyu Huang5Haiwei Wang6Pingwei Li7Xin Li8National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaNational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaState Key Laboratory of Animal Disease Control, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, ChinaDepartment of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, USANational Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, ChinaABSTRACT Nuclear cyclic GMP-AMP synthetase (cGAS) binds to nucleosome with high affinity to prevent its activation by self-DNA. Upon stimulation with double-stranded DNA, cGAS is activated and translocates from the nucleus to the cytoplasm, guided by its N-terminal domain. However, it remains unclear whether viruses can hijack cGAS translocation and regulate its activation. Here, we discovered that the protease 3C of picornavirus Seneca Valley virus (SVV) translocates from the cytoplasm to the nucleus upon viral infection and binds to nuclear DNA. Protease 3C specifically cleaves histone H2A while leaving other histone proteins unaffected. Additionally, DNA binding enhances the protease 3C’s ability to cleave nuclear cGAS, leading to its retention in the nucleus. This, in turn, suppresses the induction of type I interferon (IFN-I) following poly(dA:dT) stimulation. These findings reveal a novel mechanism by which a viral protease binds nuclear DNA, cleaves nuclear cGAS and histone H2A, and thereby mislocalizes cGAS, facilitating immune evasion.IMPORTANCECyclic GMP-AMP synthetase (cGAS) is robustly expressed in the nucleus and tightly tethered by chromatin to prevent its activation with self-DNA. During stimulation or infection, nuclear cGAS is activated and translocates from the nucleus to the cytoplasm. However, the viral strategies specifically targeting nuclear cGAS are completely unexplored. Here, we discovered that protease 3C of Seneca Valley virus translocates from the cytoplasm to the nucleus upon viral infection, binds to nuclear DNA, and specifically cleaves H2A. Furthermore, DNA binding to 3C enhances the cleavage of nuclear cGAS within its N-terminal domain. The hindrance of cGAS translocation from the nucleus to the cytoplasm results in the suppression of IFN-I induction and leads to immune evasion. This work uncovers a unique mechanism wherein a viral protease binds to nuclear DNA and cleaves nuclear cGAS and histone H2A, leading to viral evasion of cGAS-mediated immune restriction.https://journals.asm.org/doi/10.1128/mbio.03395-24nuclear cGASSeneca Valley virus3C proteasenucleosomal DNA |
| spellingShingle | Lei Wu Ya Yan Ye Yuan Zhenchao Zhao Weiyu Qu Xiangyu Huang Haiwei Wang Pingwei Li Xin Li Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon mBio nuclear cGAS Seneca Valley virus 3C protease nucleosomal DNA |
| title | Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon |
| title_full | Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon |
| title_fullStr | Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon |
| title_full_unstemmed | Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon |
| title_short | Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon |
| title_sort | viral protease binds to nucleosomal dna and cleaves nuclear cgas that attenuates type i interferon |
| topic | nuclear cGAS Seneca Valley virus 3C protease nucleosomal DNA |
| url | https://journals.asm.org/doi/10.1128/mbio.03395-24 |
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