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

The nuclear factor kB (NF-kB) pathway plays essential roles in innate and adaptive immunity, but little is known how NF-kB 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-kB. SREBP cleavage-activating protein (Scap) and sterol regulatory element-binding protein 1 (SREBP1) form a super complex with inhibitors of NF-kB a (IkBa) to associate NF-kB 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 IkBa for IkB kinase (Ikk)-mediated phosphorylation and subsequent activation of NF-kB. Loss of Scap or inhibition of S1P or S2P diminishes, while SREBP1 deficiency augments, LPS-induced NF-kB activation and subse-quent inflammatory responses. Our results reveal the Scap-SREBP1 complex as an additional cytoplasmic checkpoint for NF-kB homeostasis and unveil the Golgi apparatus as the optimal cellular platform for NF-kB activation, providing insights into the crosstalk between lipogenesis signaling and immunity.