Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages
Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages
复制标题
胆固醇稳态调节剂 SCAP-SREBP2 将 NLRP3 炎性体激活和巨噬细胞中的胆固醇生物合成信号传导整合在一起。
DOI：
10.1016/j.immuni.2018.08.021
复制
发表时间：
2018-11-20
期刊：
影响因子：
32.4
通讯作者：
Wang, Di
中科院分区：
文献类型：
--
作者：
Guo, Chuansheng;Chi, Zhexu;Wang, Di
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性小体激活的机制仍不清楚。在这里，我们已经表明，NLRP 3炎性小体激活与胆固醇主转录因子SREBP 2的成熟整合。重要的是，SCAP-SREBP2复合物内质网到高尔基体的易位是体外和体内NLRP 3炎性体最佳活化所必需的。通过固醇消耗或他汀类药物增强胆固醇生物合成信号传导促进NLPR3炎性小体活化。然而，这种调节并不主要依赖于由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，NLRP 3与SCAP-SREBP 2结合形成三元复合物，该三元复合物易位到邻近线粒体的高尔基体!用于最佳炎性小体组装的簇。我们的研究表明，除了控制胆固醇生物合成外，SCAP-SREBP2还作为巨噬细胞中整合胆固醇代谢与炎症的信号枢纽。
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 mitochondria! 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.