cGAS guards centromeric DNA to detect the virulence protein ICP0
cGAS senses viral DNA in the cytosol, leading to activation of antiviral defenses. However, most DNA viruses enter and replicate in the nucleus, where cGAS is present. How viruses may be detected by nuclear cGAS in the nucleus is ill-defined. Nuclear cGAS is maintained inactive by tethering to chromatin and is enriched on centromeric DNA. We hypothesized that centromere alterations induced by viruses might activate nuclear cGAS. The transcription activator and SUMO-targeted ubiquitin ligase ICP0 (HSV-1), disorganizes the centromere by targeting centromeric proteins. We find that ectopic expression of ICP0 in human dendritic cells induces innate immune activation, nuclear cGAMP accumulation and type III IFN production in a cGAS-dependent manner. We show that ICP0 activates cGAS independently from the MORC3 pathway. ICP0 is nuclear in DCs and leads to centromeric protein B (CENP-B) degradation. Nuclear localization and ubiquitin ligase activity of ICP0 are required for innate immune activation. ATAC-seq profiling and DNA quantification reveals that ICP0 increases respectively the accessibility and the amount of centromeric DNA (cenDNA). ICP0-induced cenDNA expansion requires DNA polymerase activity and the ICP0 target USP7 (Ubiquitin Specific Peptidase 7). Altogether, these results indicate that cGAS senses the activity of ICP0 by detecting changes in centromere DNA abundance, consistent with the guard model of pathogen detection. We propose that cGAS guards centromeric DNA in interphase to detect virulence factors.