Inflammasome complexes trigger the enzymatic activity of caspase-1, which activates interleukin-1β (IL-1β) and IL-18 (Martinon et al., 2002). Caspase-1 also targets gasdermin D, a pore-forming protein (Kayagaki et al., 2015, Shi et al., 2015). The pore-forming activity of gasdermin D resides in its N-terminal domain and is inhibited by its C-terminal domain. Caspase-1 cleaves gasdermin D at the linker region between these two domains, liberating the N-terminal domain, which migrates to the plasma membrane-forming pores with an inner diameter of 10–15 nm (Aglietti et al., 2016, Ding et al., 2016, Liu et al., 2016, Sborgi et al., 2016). An important consequence of gasdermin D activation is a lytic form of cell death called pyroptosis (He et al., 2015, Kayagaki et al., 2015, Shi et al., 2015). However, new evidence points out that gasdermin D executes additional functions independent of cell death; gasdermin D pores mediate the release of IL-1β and IL-18 without inducing cell death in response to certain ligands (Evavold et al., 2018). Additionally, after cytosolic LPS sensing by caspase-11, gasdermin D activates the NLRP3 inflammasome by inducing potassium (K+) efflux (Kayagaki et al., 2015, Rühl and Broz, 2015, Schmid-Burgk et al., 2015). Central to these distinct functions of gasdermin D is its membrane pore-forming activity. However, whether gasdermin D executes any additional immune functions is largely unknown.
A key surveillance mechanism in the cytosol, in addition to inflammasomes, is the cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) pathway. cGAS is a sensor for cytosolic DNA, and the binding of DNA by cGAS triggers its nucleotidyl transferase activity leading to the synthesis of cGAMP from ATP and GTP. cGAMP stimulates the transcription of type I interferon genes via the STING adaptor-TBK1 kinase-IRF3 transcription factor axis (Burdette et al., 2011, Wu et al., 2013). The type I interferon response elicited by cGAS plays important roles in host defense (Schneider et al., 2014). However, it is increasingly appreciated that the sustained production of type I interferons at high amounts is detrimental to the host, particularly during infections with intracellular bacteria such as Francisella novicida, Mycobacterium tuberculosis, and Listeria monocytogenes (Auerbuch et al., 2004, Henry et al., 2010, Mayer-Barber et al., 2014, McNab et al., 2015, Storek et al., 2015). Therefore, the magnitude and duration of cGAS-driven type I interferon responses should be kept in check. However, how the host restrains cGAS signaling during infections is poorly defined.
Here, we demonstrate that gasdermin D activated by the Aim2 inflammasome complex suppresses cytosolic DNA-induced production of type I interferons in macrophages. Consistent with this finding, mice lacking gasdermin D displayed enhanced IFN-β response to F. novicida infection. Pyroptosis and the extracellular release of IL-1 cytokines are dispensable for the inhibition of IFN-β by gasdermin D. Mechanistically, gasdermin D-induced membrane pores leaked intracellular potassium (K+) ions, and this K+ efflux in turn impaired type I interferon responses to cytosolic DNA and F. novicida. Gasdermin D-K+ efflux axis targeted cGAS to reduce cGAMP synthesis and thus IFN-β production. In summary, this study uncovers a previously unrecognized key role for gasdermin D in restraining cytosolic DNA-elicited interferon responses. Collectively, an emerging theme from the findings of this work and the recent studies (Evavold et al., 2018, Kayagaki et al., 2015) is that the fundamental pore-forming ability of gasdermin D and the consequent ionic fluxes confer gasdermin D additional biological functions independent of the terminal cell lytic event.