ArticlemBio2025
Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon.
Article in mBio, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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The trial behind it
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Who cites it
5 citing papers in PubMed.
- A designed peptide disrupting viral protease cleavage restores cGAS-DNA phase separation and type I interferon responses.PLoS pathogens · 2026Article
- Single-stranded nucleic acid binding enhances the in vitro catalytic activity of Chikungunya virus nsP2 protease.BBA advances · 2026Article
- Virulence determinant of Senecavirus A: 3C protein functions as a protease to cleave viral polyprotein and host factors.Virulence · 2025Review
- PRV gD-Based DNA Vaccine Candidates Adjuvanted with cGAS, UniSTING, or IFN-α Enhance Protective Immunity.Pathogens (Basel, Switzerland) · 2025Article
- Circovirus Rep evades immune restriction by disrupting cGAS oligomerization and phase separation.PLoS pathogens · 2025Article
Corrections and comments
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Authors and funding
9 authors.
Funding
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. IMPORTANCE: Cyclic 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.
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