The Scap-SREBP1-S1P/S2P lipogenesis signal orchestrates the homeostasis and spatiotemporal activation of NF-κB

Cell Rep. 2023 Jun 27;42(6):112586. doi: 10.1016/j.celrep.2023.112586. Epub 2023 Jun 1.

Abstract

The nuclear factor κB (NF-κB) pathway plays essential roles in innate and adaptive immunity, but little is known how NF-κB signaling is compartmentalized and spatiotemporally activated in the cytoplasm. Here, we show that the lipogenesis signal cascade Scap-SREBP1-S1P/S2P orchestrates the homeostasis and spatiotemporal activation of NF-κB. SREBP cleavage-activating protein (Scap) and sterol regulatory element-binding protein 1 (SREBP1) form a super complex with inhibitors of NF-κB α (IκBα) to associate NF-κB close to the endoplasmic reticulum (ER). Upon lipopolysaccharide (LPS) stimulation, Scap transports the complex to the Golgi apparatus, where SREBP1 is cleaved by site-1 protease (S1P)/S2P, liberating IκBα for IκB kinase (Ikk)-mediated phosphorylation and subsequent activation of NF-κB. Loss of Scap or inhibition of S1P or S2P diminishes, while SREBP1 deficiency augments, LPS-induced NF-κB activation and subsequent inflammatory responses. Our results reveal the Scap-SREBP1 complex as an additional cytoplasmic checkpoint for NF-κB homeostasis and unveil the Golgi apparatus as the optimal cellular platform for NF-κB activation, providing insights into the crosstalk between lipogenesis signaling and immunity.

Keywords: CP: Immunology; inflammation; metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Homeostasis
  • Humans
  • Lipogenesis*
  • Lipopolysaccharides / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice
  • NF-KappaB Inhibitor alpha / metabolism
  • NF-kappa B* / metabolism
  • Sterol Regulatory Element Binding Protein 1 / metabolism

Substances

  • Lipopolysaccharides
  • membrane-bound transcription factor peptidase, site 1
  • NF-kappa B
  • NF-KappaB Inhibitor alpha
  • SREBP cleavage-activating protein
  • Sterol Regulatory Element Binding Protein 1
  • MBTPS2 protein, human