The inflammasomes are multiprotein complexes sensing tissue damage and infectious agents to initiate innate immune responses. Different inflammasomes containing distinct sensor molecules exist. The NLRP3 inflammasome is unique as it detects a variety of danger signals. It has been reported that NLRP3 is recruited to mitochondria-associated endoplasmic reticulum membranes (MAMs) and is activated by MAM-derived effectors. Here, we show that in response to inflammasome activators, MAMs localize adjacent to Golgi membranes. Diacylglycerol (DAG) at the Golgi rapidly increases, recruiting protein kinase D (PKD), a key effector of DAG. Upon PKD inactivation, self-oligomerized NLRP3 is retained at MAMs adjacent to Golgi, blocking assembly of the active inflammasome. Importantly, phosphorylation of NLRP3 by PKD at the Golgi is sufficient to release NLRP3 from MAMs, resulting in assembly of the active inflammasome. Moreover, PKD inhibition prevents inflammasome autoactivation in peripheral blood mononuclear cells from patients carrying NLRP3 mutations. Hence, Golgi-mediated PKD signaling is required and sufficient for NLRP3 inflammasome activation.

炎性小体是感测组织损伤的多种蛋白复合物和可引发先天性免疫反应的感染因子。存在包含不同传感器分子的不同炎症小体。NLRP3炎性小体非常独特，因为它可以检测各种危险信号。据报道，NLRP3被募集到与线粒体相关的内质网膜（MAM），并被MAM衍生的效应子激活。在这里，我们表明，响应炎症小体激活剂，MAM位于高尔基体膜附近。高尔基体中的二酰基甘油（DAG）快速增加，募集了DAG的关键效应蛋白激酶D（PKD）。PKD失活后，自寡聚的NLRP3保留在与高尔基体相邻的MAM处，阻止了活性炎症小体的组装。重要的，高尔基体上PKD对NLRP3的磷酸化足以从MAM中释放NLRP3，从而导致活性炎症小体的组装。此外，PKD抑制可防止携带NLRP3突变的患者外周血单核细胞中的炎性体自激活。因此，高尔基体介导的PKD信号是必需的，并且对于NLRP3炎性体激活是足够的。