Journal Article

Viral protease binds to nucleosomal DNA and cleaves nuclear cGAS that attenuates type I interferon

Yan, Ya, Yuan, Ye, Li, Pingwei, Qu, Weiyu, Zhao, Zhenchao, Huang, Xiangyu, Wang, Haiwei, Wu, Lei, Li, Xin

2025

Overview

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.

• Publisher: American Society for Microbiology
• Subject: 3C protease / 3C Viral Proteases - metabolism / Cell Nucleus - metabolism / Chromatin / Cyclic GMP / Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase / Cytoplasm / Cytoplasm - metabolism / Dengue fever / Deoxyribonucleic acid / DNA / DNA - metabolism / Histone H2A / Histones - metabolism / Host-Microbial Interactions / Humans / Immune Evasion / Interferon / Interferon Type I - immunology / Interferon Type I - metabolism / Kinases / Localization / Microscopy / Mitochondrial DNA / nuclear cGAS / nucleosomal DNA / Nucleosomes - metabolism / Nucleotidyltransferases - genetics / Nucleotidyltransferases - metabolism / Protein Binding / Research Article / Seneca Valley virus / Viral infections / Viruses