Gasdermin D Restrains Type I Interferon Response to Cytosolic DNA by Disrupting Ionic Homeostasis
Department of Medicine, Division of Infectious Diseases and Immunology
Immunology and Infectious Disease
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-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.
DOI of Published Version
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
Banerjee I, Behl B, Mendonca M, Shrivastava G, Russo AJ, Menoret A, Ghosh A, Vella AT, Vanaja SK, Sarkar SN, Fitzgerald KA, Rathinam VA. (2018). Gasdermin D Restrains Type I Interferon Response to Cytosolic DNA by Disrupting Ionic Homeostasis. Infectious Diseases and Immunology Publications. https://doi.org/10.1016/j.immuni.2018.07.006. Retrieved from https://escholarship.umassmed.edu/infdis_pp/422