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. Epub 2018 Oct 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cholesterol / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Golgi Apparatus / metabolism
  • Humans
  • Inflammasomes / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Processing, Post-Translational
  • Protein Transport
  • Proteolysis
  • Signal Transduction*
  • Sterol Regulatory Element Binding Protein 2 / metabolism*

Substances

  • Inflammasomes
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • SREBF2 protein, human
  • SREBP cleavage-activating protein
  • Sterol Regulatory Element Binding Protein 2
  • Cholesterol