The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation.
The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation.
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DOI：
10.1038/ncomms15556
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发表时间：
2017-06-05
影响因子：
16.6
通讯作者：
Stehlik C
中科院分区：
文献类型：
--
作者：
Ratsimandresy RA;Chu LH;Khare S;de Almeida L;Gangopadhyay A;Indramohan M;Misharin AV;Greaves DR;Perlman H;Dorfleutner A;Stehlik C
炎性小体是将细胞溶质感觉蛋白识别微生物、病原体相关和损伤相关的分子模式与半胱天冬酶-1激活相联系的蛋白质平台。半胱天冬酶-1促进热性细胞死亡以及白细胞介素（IL）-1β和IL-18的成熟和分泌，从而引发炎症反应以清除感染并启动伤口愈合;然而，过度反应会导致炎症性疾病。炎性小体组装需要含有PYRIN结构域（PYD）的衔接子ASC，并且依赖于PYD-PYD相互作用。在这里，我们表明，PYD唯一的蛋白POP 2抑制炎性小体组装通过结合ASC和干扰ASC的募集上游传感器，这阻止caspase-1激活和细胞因子释放。POP 2还通过抑制非经典IκB激酶β和IκBα的活化来削弱巨噬细胞的启动，从而在体内保护免于过度炎症和急性休克。我们的研究结果推进了我们对维持平衡炎症反应的复杂调控机制的理解，并突出了各个POP成员之间的重要差异。过度的炎性小体激活导致炎性疾病，但炎性小体如何被仅PYD的衔接子调节尚不清楚。在这里，作者表明仅PYD蛋白POP 2通过分别干扰IκBα激活和NLRP 3-ASC相互作用来抑制炎性小体引发和组装。
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. Excessive inflammasome activation leads to inflammatory diseases, but how inflammasomes are regulated by PYD-only adaptors is unclear. Here the authors show that the PYD-only protein POP2 inhibits both inflammasome priming and assembly by interfering, respectively, with IκBα activation and NLRP3-ASC interaction.