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Cholesterol Homeostatic Regulator SCAP-SREBP2 Integrates NLRP3 Inflammasome Activation and Cholesterol Biosynthetic Signaling in Macrophages
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.
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SCAP is a cholesterol sensor that regulates intracellular cholesterol homeostasis through signal transduction.
“Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a cholesterol sensor that regulates intracellular cholesterol homeostasis through signal transduction16–18.”
The ER-to-Golgi translocation of the SCAP-SREBP2 complex is required for full activation of NLRP3.
“Notably, Guo et al. demonstrated that the ER-to-Golgi translocation of the SCAP–SREBP2 complex was required for the full activation of the NLRP318.”
Reduced INSIG1 expression activates SREBP2, leading to upregulated expression of inflammatory cytokines in macrophages, such as IL-1β, CXCL10, and CXCL11, independent of the cholesterol synthesis pathway.
“Moreover, reduced INSIG1 expression activates SREBP2, leading to upregulated expression of inflammatory cytokines in macrophages, such as IL-1β, C-X-C motif chemokine ligand 10 (CXCL10), and CXCL11, independent of the cholesterol synthesis pathway33,34.”
From Macrophage INSIG1 deficiency drives psoriasiform dermatitis via the SREBP2-STAT1 axis (2026) · cites this paper as [34]
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Metadata
- Authors
- Guo, C., Chi, Z., Jiang, D., Xu, T., Yu, W., Wang, Z., Chen, S., Zhang, L., Liu, Q., Guo, X., Zhang, X., Li, W., Lu, L., Wu, Y., Song, B.-L., & Wang, D.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 49
- Issue
- 5
- Pages
- 842-856.e7
- ISSN
- 1074-7613
- Cited by
- 325
- References
- 9
- Language
- en
- Licence
- Funders
- National Natural Science Foundation of China (81730047, 31522020, 31670926)
- National Key Research and Development Program of China (2018YFC1105203, 2016YFC1100204)
- Fundamental Research Funds for the Central Universities (2015XZZX004-31)
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