2. Academic Validation
  3. 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

  • Immunity. 2018 Nov 20;49(5):842-856.e7. doi: 10.1016/j.immuni.2018.08.021.
Chuansheng Guo 1,  Zhexu Chi 1,  Danlu Jiang 1,  Ting Xu 1,  Weiwei Yu 2,  Zhen Wang 1,  Sheng Chen 1,  Li Zhang 1,  Qianyun Liu 2,  Xingchen Guo 2,  Xue Zhang 3,  Wenxin Li 2,  Linrong Lu 1,  Yingliang Wu 2,  Bao-Liang Song 4,  Di Wang 5
Affiliations

Affiliations

  • 1 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.
  • 2 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
  • 3 Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 4 Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, P.R. China.
  • 5 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. Electronic address: diwang@zju.edu.cn.
PMID: 30366764 DOI: 10.1016/j.immuni.2018.08.021
Abstract

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.

Keywords

NLRP3 inflammasome; SCAP; SREBP2; cholesterol biosynthetic signaling; inflammation; statins.

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