Aicardi-Goutières syndrome (AGS) is a rare genetic condition associated with brain inflammation in children and is associated with a Type 1 Interferon response. AGS can be viewed as a genetic mimic of congenital viral infection. Mutations in ribonuclease H2 (RNase H2) genes, which code for an enzyme that is vital for genome stability, are the most common cause of AGS. We have previously shown that immune activation in RNase H2 deficiency is associated with triggering of the DNA sensor cGAS and its adaptor protein STING. This raised the important question of how cGAS is activated in RNase H2 deficiency.
We observed cGAS localising to structures known as micronuclei within RNase H2 deficient cells. Micronuclei are formed during mis-segregation of DNA during mitosis, are associated with genome instability and are often a feature in tumour cells. cGAS localisation to micronuclei was not restricted to RNase H2 deficiency, also occurring following exogenous irradiation-induced DNA damage and in micronuclei arising spontaneously in human cancer cells. Breakdown of the micronuclear envelope resulted in rapid accumulation of cGAS, providing an explanation of how cytosolic cGAS gains access to this immunostimulatory DNA. Furthermore, live-cell laser microdissection and single cell transcriptomics showed that interferon-stimulated gene expression was preferentially induced in cells with micronuclei. These findings support a cell-intrinsic immune surveillance mechanism which could detect a range of neoplasia promoting processes, but where aberrant activation triggers autoinflammatory disease (Mackenzie KJ et al, Nature;548:461).