Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Nat Commun. 2017 Jun 5;8:15556. doi: 10.1038/ncomms15556.
Inflammasomes are protein platforms linking recognition of microbe, pathogen-associated and damage-associated molecular patterns by cytosolic sensory proteins to caspase-1 activation. Caspase-1 promotes pyroptotic cell death and the maturation and secretion of interleukin (IL)-1β and IL-18, which trigger inflammatory responses to clear infections and initiate wound-healing; however, excessive responses cause inflammatory disease. Inflammasome assembly requires the PYRIN domain (PYD)-containing adaptor ASC, and depends on PYD-PYD interactions. Here we show that the PYD-only protein POP2 inhibits inflammasome assembly by binding to ASC and interfering with the recruitment of ASC to upstream sensors, which prevents caspase-1 activation and cytokine release. POP2 also impairs macrophage priming by inhibiting the activation of non-canonical IκB kinase ɛ and IκBα, and consequently protects from excessive inflammation and acute shock in vivo. Our findings advance our understanding of the complex regulatory mechanisms that maintain a balanced inflammatory response and highlight important differences between individual POP members.
炎性小体是一种蛋白平台，可将胞质感觉蛋白对微生物、病原体相关和损伤相关分子模式的识别与半胱天冬酶-1 的激活联系起来。半胱天冬酶-1 促进细胞焦亡和白细胞介素 (IL)-1β 和 IL-18 的成熟和分泌，从而引发清除感染和启动伤口愈合的炎症反应；然而，过度的反应会导致炎症性疾病。炎性小体的组装需要包含 PYRIN 结构域 (PYD) 的衔接蛋白 ASC，并且依赖于 PYD-PYD 相互作用。在这里，我们表明，仅含有 PYD 的蛋白 POP2 通过与 ASC 结合并干扰 ASC 招募到上游传感器来抑制炎性小体的组装，从而阻止半胱天冬酶-1 的激活和细胞因子的释放。POP2 还通过抑制非典型 IκB 激酶ɛ和 IκBα 的激活来损害巨噬细胞的启动，从而在体内防止过度炎症和急性休克。我们的发现增进了我们对维持平衡炎症反应的复杂调节机制的理解，并突出了个体 POP 成员之间的重要差异。
