NLRP3 recruitment by NLRC4 during Salmonella infection.
NLRP3 recruitment by NLRC4 during Salmonella infection.
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DOI：
10.1084/jem.20132234
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发表时间：
2016-05-30
期刊：
影响因子：
--
通讯作者：
Dixit VM
中科院分区：
文献类型：
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作者：
Qu Y;Misaghi S;Newton K;Maltzman A;Izrael-Tomasevic A;Arnott D;Dixit VM
Dixit等人通过设计一种保留NLRC4支架功能的突变小鼠品系，展示了它与另一种NOD家族传感器NLRP3之间的协同性。NLRC4和NLRP3是nod样受体（NLR）细胞内蛋白家族的成员，在先天免疫细胞中表达，被认为形成不同的炎性小体复合物，促进caspase-1激活，促炎细胞因子IL-1β和IL-18的分泌，以及一种称为焦亡的细胞死亡形式。我们发现，在感染鼠伤寒沙门氏菌或转染鞭毛蛋白的巨噬细胞中，NLRP3与NLRC4存在关联。当表达磷酸化位点突变体NLRC4 S533A的Nlrc4S533A/S533A骨髓源性巨噬细胞（BMDMs）与NLRC4缺失的BMDMs相比，在caspase-1激活方面只有轻微缺陷时，NLRC4 NACHT结构域与NLRP3相互作用的意义被揭示。NLRC4 S533A通过募集NLRP3及其接头蛋白ASC激活caspase-1。因此，Nlrc4S533A/S533A Nlrp3−/−BMDMs对鼠伤寒沙门氏菌或鞭毛蛋白的反应更接近Nlrc4−/−BMDMs。NLRP3和NLRC4之间的相互作用揭示了被认为不同的炎性小体支架之间意想不到的重叠。
By engineering a mutant mouse strain that preserves the scaffolding function of NLRC4, Dixit et al. show cooperativity between it and another NOD family sensor, NLRP3. NLRC4 and NLRP3, of the NOD-like receptor (NLR) family of intracellular proteins, are expressed in innate immune cells and are thought to nucleate distinct inflammasome complexes that promote caspase-1 activation, secretion of the proinflammatory cytokines IL-1β and IL-18, and a form of cell death termed pyroptosis. We show that NLRP3 associates with NLRC4 in macrophages infected with Salmonella typhimurium or transfected with flagellin. The significance of the interaction between the NLRC4 NACHT domain and NLRP3 was revealed when Nlrc4S533A/S533A bone marrow–derived macrophages (BMDMs) expressing phosphorylation site mutant NLRC4 S533A had only a mild defect in caspase-1 activation when compared with NLRC4-deficient BMDMs. NLRC4 S533A activated caspase-1 by recruiting NLRP3 and its adaptor protein ASC. Thus, Nlrc4S533A/S533A Nlrp3−/− BMDMs more closely resembled Nlrc4−/− BMDMs in their response to S. typhimurium or flagellin. The interplay between NLRP3 and NLRC4 reveals an unexpected overlap between what had been considered distinct inflammasome scaffolds.