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

Immunity. 2018 Sep 18;49(3):413-426.e5. doi: 10.1016/j.immuni.2018.07.006. Epub 2018 Aug 28.


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.

Keywords: Francisella; IFN-β; K(+); STING; cGAS; caspase-1; cytosolic DNA; gasdermin D; inflammasome; poly(dA:dT); potassium.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • DNA Damage
  • DNA-Binding Proteins / metabolism
  • Francisella / physiology*
  • Gram-Negative Bacterial Infections / immunology*
  • HEK293 Cells
  • Humans
  • Inflammasomes / metabolism*
  • Interferon Type I / metabolism
  • Interleukin-1 / metabolism
  • Interleukin-18 / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Phosphate-Binding Proteins
  • Potassium / metabolism
  • RNA, Small Interfering / genetics


  • AIM2 protein, human
  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • Gsdmd protein, mouse
  • Inflammasomes
  • Interferon Type I
  • Interleukin-1
  • Interleukin-18
  • Intracellular Signaling Peptides and Proteins
  • Phosphate-Binding Proteins
  • RNA, Small Interfering
  • Potassium