Facultad de Biología, Departamento de Biología Celular e Histología, Universidad de Murcia, IMIB-Arrixaca, 30100 Murcia, Spain.
Instituto de Investigaciones Marinas, CSIC, 36208 Vigo, Spain.
Nat Commun. 2016 Jul 1;7:12077. doi: 10.1038/ncomms12077.
Inflammasomes are cytosolic molecular platforms that alert the immune system about the presence of infection. Here we report that zebrafish guanylate-binding protein 4 (Gbp4), an IFNγ-inducible GTPase protein harbouring a C-terminal CARD domain, is required for the inflammasome-dependent clearance of Salmonella Typhimurium (ST) by neutrophils in vivo. Despite the presence of the CARD domain, Gbp4 requires the universal inflammasome adaptor Asc for mediating its antibacterial function. In addition, the GTPase activity of Gbp4 is indispensable for inflammasome activation and ST clearance. Mechanistically, neutrophils are recruited to the infection site through the inflammasome-independent production of the chemokine (CXC motif) ligand 8 and leukotriene B4, and then mediate bacterial clearance through the Gbp4 inflammasome-dependent biosynthesis of prostaglandin D2. Our results point to GBPs as key inflammasome adaptors required for prostaglandin biosynthesis and bacterial clearance by neutrophils and suggest that transient activation of the inflammasome may be used to treat bacterial infections.
炎症小体是一种细胞溶质分子平台，可提示免疫系统存在感染。在这里，我们报告说，斑马鱼鸟苷酸结合蛋白 4（Gbp4），一种 IFNγ诱导的 GTPase 蛋白，具有 C 末端 CARD 结构域，是中性粒细胞体内依赖炎症小体清除沙门氏菌 Typhimurium（ST）所必需的。尽管存在 CARD 结构域，但 Gbp4 需要普遍的炎症小体衔接蛋白 Asc 来介导其抗菌功能。此外，Gbp4 的 GTPase 活性对于炎症小体的激活和 ST 的清除是必不可少的。从机制上讲，通过炎症小体非依赖性产生趋化因子（CXC 基序）配体 8 和白三烯 B4 将中性粒细胞募集到感染部位，然后通过 Gbp4 炎症小体依赖性合成前列腺素 D2 来介导细菌清除。我们的结果表明，GBPs 是中性粒细胞合成前列腺素和清除细菌所必需的关键炎症小体衔接蛋白，并表明炎症小体的短暂激活可用于治疗细菌感染。
