Immunity ( IF 25.5 ) Pub Date : 2018-08-28 , DOI: 10.1016/j.immuni.2018.07.006
Ishita Banerjee , Bharat Behl , Morena Mendonca , Gaurav Shrivastava , Ashley J. Russo , Antoine Menoret , Arundhati Ghosh , Anthony T. Vella , Sivapriya Kailasan Vanaja , Saumendra N. Sarkar , Katherine A. Fitzgerald , Vijay A.K. Rathinam
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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.
中文翻译:
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Gasdermin D通过破坏离子稳态来抑制I型干扰素对胞质DNA的反应。
炎症小体激活的caspase-1裂解gasdermin D以掩盖其成孔活性,其主要结果是发烧。在这里,我们报告胃泌素D在限制细胞溶质DNA监测中的其他生物学作用。胞质DNA被Aim2和环状GMP-AMP合酶(cGAS)感应,分别导致炎症小体和I型干扰素反应。我们发现,由Aim2炎性体激活的加德敏D抑制了巨噬细胞中cGAS驱动的I型干扰素对细胞质DNA和新生弗朗西斯菌的反应。同样,干扰素-β(IFN-β)对诺维氏菌的反应Gasdermin D缺陷小鼠的感染率升高。Gasdermin D介导的IFN-β负调节以不依赖于光解,白介素1(IL-1)和IL-18的方式发生。从机制上讲,加德敏D通过膜孔消耗了细胞内钾(K +),并且这种K +流出对于抑制cGAS依赖性IFN-β反应是必要且充分的。因此,我们的发现发现了涉及加德敏D和K +外排的其他干扰素调节模块。