Nuclear soluble cGAS senses DNA virus infection

Abstract

Abstract The DNA sensor cGAS detects cytosolic foreign DNA from pathogens or self-DNA from cellular damage and instigates type I interferon (IFN) expression. Recent studies find that cGAS also localizes in the nucleus and tethers to the chromatin. Despite how cGAS is inhibited in the nucleus is well elucidated, whether nuclear cGAS participates in DNA sensing is not clear. Here, we report that herpes simplex virus 1 (HSV-1) infection causes the release of cGAS from the chromatin into the nuclear soluble fraction, and the free nuclear cGAS senses viral DNA to induce innate immune response. We first found that the infection of several HSV-1 strains led to cGAS release from the chromatin in several types of cells, including in RAW264.7 macrophages, THP-1 monocytes, and bone marrow-derived macrophages. DNA damage agent cisplatin failed to induce nuclear soluble cGAS, suggesting that cGAS release from the chromatin is not due to DNA damage or apoptosis. Interestingly, inhibition of HSV-1 replication blocked the release of nuclear soluble cGAS. To determine the role of nuclear cGAS in DNA virus infection, we reconstituted a Dox-induced nuclear-only cGAS mutant into cGAS knockout RAW264.7 cells. After induction, only chromatin-bound cGAS was found in the reconstituted cells. Similarly, HSV-1 infected also induced nuclear soluble cGAS in this cell line. More importantly, the nuclear-only cGAS stable cells limited HSV-1 infection by producing cGAMP and inducing mRNA expression of type I IFN and interferon-stimulated genes. Taken all together, our study demonstrates that nuclear soluble cGAS is a DNA sensor inside the nucleus. This research was funded by the National Institutes of Health (R21AI137750 and R01AI141399 to S.L.).