Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages

• Published in: Immunity (Cambridge, Mass.) Vol. 49; no. 5; pp. 842 - 856.e7
• Main Authors: Guo, Chuansheng, Chi, Zhexu, Jiang, Danlu, Xu, Ting, Yu, Weiwei, Wang, Zhen, Chen, Sheng, Zhang, Li, Liu, Qianyun, Guo, Xingchen, Zhang, Xue, Li, Wenxin, Lu, Linrong, Wu, Yingliang, Song, Bao-Liang, Wang, Di
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-11-2018; Elsevier Limited
• Subjects: Animals; Biosynthesis; Cell activation; Cell Line; Cholesterol; Cholesterol - metabolism; cholesterol biosynthetic signaling; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Experiments; Golgi apparatus; Golgi Apparatus - metabolism; Homeostasis; Humans; Inflammasomes; Inflammasomes - metabolism; inflammation; Intracellular Signaling Peptides and Proteins - metabolism; Lipid metabolism; Macrophages; Macrophages - immunology; Macrophages - metabolism; Membrane Proteins - metabolism; Metabolism; Metabolites; Mice; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Protein Binding; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Protein Transport; Proteins; Proteolysis; R&D; Research & development; SCAP; Signal Transduction; Signaling; SREBP2; Statins; Statistical analysis; Sterol Regulatory Element Binding Protein 2 - metabolism; Sterols; Translocation; China; SREBP2; SCAP; cholesterol biosynthetic signaling; NLRP3 inflammasome; inflammation; statins
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.08.021

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.
[Display omitted]
•NLRP3 inflammasome activation couples SREBP2 maturation•SCAP-SREBP2 translocation and S1P are required for optimal NLRP3 inflammasome activity•SCAP escorts both NLRP3 and SREBP2 by forming a ternary complex•SCAP-SREBP2 inhibition protects mice from systemic inflammation
The metabolic-inflammatory crosstalk plays a key role in host defense against pathogens and inflammation. Guo and colleagues demonstrate that SCAP-SREBP2 complex integrates NLRP3 inflammasome activation and cholesterol biosynthetic signaling during inflammation.