Gasdermin D Restrains Type I Interferon Response to Cytosolic DNA by Disrupting Ionic Homeostasis
Russo, Ashley J.
Vella, Anthony T.
Vanaja, Sivapriya Kailasan.
Sarkar, Saumendra N.
Fitzgerald, Katherine A.
Rathinam, Vijay A. K
UMass Chan AffiliationsDepartment of Medicine, Division of Infectious Diseases and Immunology
KeywordsImmunology and Infectious Disease
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AbstractInflammasome-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-beta (IFN-beta) response to F. novicida infection was elevated in gasdermin D-deficient mice. Gasdermin D-mediated negative regulation of IFN-beta 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-beta response. Thus, our findings have uncovered an additional interferon regulatory module involving gasdermin D and K(+) efflux.
Banerjee I, Behl B, Mendonca M, Shrivastava G, Russo AJ, Menoret A, Ghosh A, Vella AT, Vanaja SK, Sarkar SN, Fitzgerald KA, Rathinam VAK. 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. PMID: 30170814; PMCID: PMC6347470. Link to article on publisher's site