Cell Reports (Jun 2023)

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

  • Xia Fei,
  • Jiaqi Huang,
  • Fei Li,
  • Yuejue Wang,
  • Zhehua Shao,
  • Lingling Dong,
  • Yinfang Wu,
  • Boran Li,
  • Xue Zhang,
  • Baihui Lv,
  • Yun Zhao,
  • Qingyu Weng,
  • Kaijun Chen,
  • Min Zhang,
  • Shiyi Yang,
  • Chao Zhang,
  • Min Zhang,
  • Wen Li,
  • Songmin Ying,
  • Qiming Sun,
  • Zhihua Chen,
  • Huahao Shen

Journal volume & issue
Vol. 42, no. 6
p. 112586

Abstract

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Summary: 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.

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