1. Gasdermin D Restrains Type I Interferon Response to Cytosolic DNA by Disrupting Ionic Homeostasis.
- Author
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Banerjee I, Behl B, Mendonca M, Shrivastava G, Russo AJ, Menoret A, Ghosh A, Vella AT, Vanaja SK, Sarkar SN, Fitzgerald KA, and Rathinam VAK
- Subjects
- Animals, Apoptosis, Apoptosis Regulatory Proteins genetics, DNA Damage, DNA-Binding Proteins metabolism, HEK293 Cells, Humans, 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, Apoptosis Regulatory Proteins metabolism, Francisella physiology, Gram-Negative Bacterial Infections immunology, Inflammasomes metabolism
- 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., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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