Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection

Viral infection triggers host innate immune responses that result in the production of various cytokines including type I interferons (IFN), activation of inflammasomes, and programmed cell death of the infected cells. Tight control of inflammatory cytokine production is crucial for the triggering of an effective immune response that can resolve the infection without causing host pathology. In examining the inflammatory response of Asc−/− and Casp1−/− macrophages, we found that deficiency in these molecules resulted in increased IFN production upon DNA virus infection, but not RNA virus challenge. Investigation of the underlying mechanism revealed that upon canonical and non-canonical inflammasome activation, caspase-1 interacted with cyclic GMP-AMP (cGAMP) synthase (cGAS), cleaving it and dampening cGAS-STING-mediated IFN production. Deficiency in inflammasome signaling enhanced host resistance to DNA virus in vitro and in vivo, and this regulatory role extended to other inflammatory caspases. Thus, inflammasome activation dampens cGAS-dependent signaling, suggesting cross-regulation between intracellular DNA-sensing pathways. [Display omitted] •IFN production by Asc−/− and Casp1−/− macrophages is elevated upon DNA virus infection•Caspase-1 cuts cGAS during DNA virus infection, but not RNA virus challenge•Caspase-4, 5, and 11 cut cGAS in conditions of non-canonical inflammasome activation•cGAS N-terminal R/K-rich region is essential for its physiological function Type I interferons (IFN) can inhibit inflammasome activation. Wang et al. find that upon inflammasome activation, inflammatory caspases cleave cGAS and render it inactive. Their findings reveal a role for inflammasomes in the dampening of IFN activating pathways and suggest a double-negative feedback loop that regulates the output of DNA-sensing pathways.