Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
Immunity. 2018 Nov 20;49(5):842-856.e7. doi: 10.1016/j.immuni.2018.08.021. Epub 2018 Oct 23.
Cholesterol metabolism has been linked to immune functions, but the mechanisms by which cholesterol biosynthetic signaling orchestrates inflammasome activation remain unclear. Here, we have shown that NLRP3 inflammasome activation is integrated with the maturation of cholesterol master transcription factor SREBP2. Importantly, SCAP-SREBP2 complex endoplasmic reticulum-to-Golgi translocation was required for optimal activation of the NLRP3 inflammasome both in vitro and in vivo. Enforced cholesterol biosynthetic signaling by sterol depletion or statins promoted NLPR3 inflammasome activation. However, this regulation did not predominantly depend on changes in cholesterol homeostasis controlled by the transcriptional activity of SREBP2, but relied on the escort activity of SCAP. Mechanistically, NLRP3 associated with SCAP-SREBP2 to form a ternary complex which translocated to the Golgi apparatus adjacent to a mitochondrial cluster for optimal inflammasome assembly. Our study reveals that, in addition to controlling cholesterol biosynthesis, SCAP-SREBP2 also serves as a signaling hub integrating cholesterol metabolism with inflammation in macrophages.
胆固醇代谢与免疫功能有关，但胆固醇生物合成信号协调炎症小体激活的机制尚不清楚。在这里，我们表明 NLRP3 炎症小体的激活与胆固醇主转录因子 SREBP2 的成熟相整合。重要的是，SCAP-SREBP2 复合物内质网到高尔基体的易位对于 NLRP3 炎症小体在体外和体内的最佳激活是必需的。固醇耗竭或他汀类药物增强的胆固醇生物合成信号促进了 NLPR3 炎症小体的激活。然而，这种调节主要不依赖于 SREBP2 的转录活性控制的胆固醇稳态的变化，而是依赖于 SCAP 的护送活性。从机制上讲，NLRP3 与 SCAP-SREBP2 形成三元复合物，该复合物转位到与线粒体簇相邻的高尔基体，以进行最佳的炎症小体组装。我们的研究表明，除了控制胆固醇生物合成外，SCAP-SREBP2 还可作为一个信号枢纽，将胆固醇代谢与巨噬细胞中的炎症联系起来。
