Gasdermin D Restrains Type I Interferon Response to Cytosolic DNA by Disrupting Ionic Homeostasis

Abstract

Inflammasome-activated caspase-1 cleaves gasdermin D to unmask its pore-forming activity, the predominant consequence of which is pyroptosis. Here, we report an additional biological role for gasdermin D in limiting cytosolic DNA surveillance. Cytosolic DNA is sensed by Aim2 and cyclic GMP-AMP synthase (cGAS) leading to inflammasome and type I interferon responses, respectively. We found that gasdermin D activated by the Aim2 inflammasome suppressed cGAS-driven type I interferon response to cytosolic DNA and Francisella novicida in macrophages. Similarly, interferon-β (IFN-β) response to F. novicida infection was elevated in gasdermin D-deficient mice. Gasdermin D-mediated negative regulation of IFN-β occurred in a pyroptosis-, interleukin-1 (IL-1)-, and IL-18-independent manner. Mechanistically, gasdermin D depleted intracellular potassium (K) via membrane pores, and this K efflux was necessary and sufficient to inhibit cGAS-dependent IFN-β response. Thus, our findings have uncovered an additional interferon regulatory module involving gasdermin D and K efflux.

STING pathway agonism as a cancer therapeutic

“…Following non‐canonical inflammasome activation induced by LPS, caspases 5,6, and 11 were also capable of cleaving cGAS. Potassium influx following caspase‐1 cleavage of gasdermin D directly inhibits cGAS enzyme activity . Antiviral and inflammasome programs appear to be mutually inhibitory, as type I IFNs down regulate the NLRP1 and NLRP3 inflammasomes via STAT1 and IL10/STAT3 signaling to reduce pro‐IL1 production .…”

“…Potassium influx following caspase-1 cleavage of gasdermin D directly inhibits cGAS enzyme activity. 77 Antiviral and inflammasome programs appear to be mutually inhibitory, as type I IFNs down regulate the NLRP1 and NLRP3 inflammasomes via STAT1 and IL10/STAT3 signaling to reduce pro-IL1 production. 78,79 NLRC3, which is an inflammasome component, also reduces STING translocation and association with TBK1.…”

Canonical and noncanonical inflammasomes in intestinal epithelial cells

“…GSDMD's role in forming pores and inducing pyroptosis is well established (Shi et al, 2015). However, recent evidence has emerged indicating that GSDMD pores do not inherently result in cell death (Banerjee et al, 2018;de Vasconcelos, Van Opdenbosch, Van Gorp, Parthoens, & Lamkanfi, 2019;Russo et al, 2016). Pore formation prior to cell death has been shown to mediate IL-1β and IL-18 secretion, and Ca 2+ influx through these pores can activate the ESCRT-III machinery, which repairs the damaged membrane and prevents cell lysis (Evavold et al, 2018;Rühl et al, 2018).…”

The rOX‐stars of inflammation: links between the inflammasome and mitochondrial meltdown

“…83 Host mtDNA is recognised by cGAS to drive cGAMP/STING-mediated IFN-b antiviral signalling. 82,[84][85][86] While AIM2 inflammasome activation inhibits cGAS signalling via GSDMDdependent K + efflux, 87 cGAS/STING-dependent NF-jB activation may provide a signal 1 for NLRP3 inflammasome activation. cGAS/STING signalling may also be a downstream consequence of NLRP3 activation; for example, IL-1R signalling in the human THP-1 myeloid cell line drives loss of mitochondrial membrane potential and recognition of mtDNA by cGAS.…”