Immunity
Volume 49, Issue 3, 18 September 2018, Pages 413-426.e5
Journal home page for Immunity

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

https://doi.org/10.1016/j.immuni.2018.07.006Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Inflammasome-activated gasdermin D limits type I interferon responses to cytosolic DNA

  • Gasdermin D targets cGAS activation to inhibit IFN-β response to cytosolic DNA

  • Depletion of intracellular K+ by gasdermin D is responsible for limiting cGAS signaling

  • K+ efflux is sufficient to inhibit cGAS-dependent type I interferon responses

Summary

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

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

Cited by (0)

7

Lead Contact