The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease.
The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease.
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DOI：
10.1016/j.immuni.2015.07.018
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发表时间：
2015-08-18
期刊：
影响因子：
32.4
通讯作者：
Stehlik C
中科院分区：
文献类型：
--
作者：
de Almeida L;Khare S;Misharin AV;Patel R;Ratsimandresy RA;Wallin MC;Perlman H;Greaves DR;Hoffman HM;Dorfleutner A;Stehlik C
为了应对感染和组织损伤，含有asc的炎症体蛋白复合体被组装在一起，促进caspase-1激活、IL-1β和IL-18的处理和释放、下垂和asc颗粒的释放。然而，炎症小体的过度或持续激活会导致炎症性疾病。因此，平衡的炎症体反应对维持体内平衡至关重要。我们发现，只有PYD的蛋白POP1通过阻止炎性小体成核来抑制依赖于ASC的炎性小体组装，从而干扰Caspase-1的激活、IL-1β和IL-18的释放、下垂和ASC颗粒的释放。POP1基因在小鼠中没有同源基因，但人POP1在单核细胞、巨噬细胞和树突状细胞中的转基因表达可以保护小鼠免受分子PAMPs、炎症体成分NLRP3突变和ASC危险颗粒引发的全身炎症。POP1的表达受TLR和IL-1R信号的调节，我们认为POP1提供了一个调节反馈环，关闭了过度的炎症反应，从而防止了全身炎症。
In response to infections and tissue damage, ASC-containing inflammasome protein complexes are assembled that promote caspase-1 activation, IL-1β and IL-18 processing and release, pyroptosis, and the release of ASC particles. However, excessive or persistent activation of the inflammasome causes inflammatory diseases. Therefore, a well-balanced inflammasome response is crucial to maintain homeostasis. We show that the PYD-only protein POP1 inhibited ASC-dependent inflammasome assembly by preventing inflammasome nucleation, and consequently interfered with caspase-1 activation, IL-1β and IL-18 release, pyroptosis and the release of ASC particles. There is no mouse ortholog for the POP1 gene, but transgenic expression of human POP1 in monocytes, macrophages and dendritic cells protected mice from systemic inflammation triggered by molecular PAMPs, inflammasome component NLRP3 mutation and ASC danger particles. POP1 expression was regulated by TLR- and IL-1R–signalling, and we propose that POP1 provides a regulatory feedback loop that shuts down excessive inflammatory responses and thereby prevents systemic inflammation.