Abstract
The sterol-regulatory element binding proteins (SREBP) are central transcriptional regulators of lipid metabolism. Using haploid genetic screens we identify the SREBPRegulating Gene (SPRING/C12ORF49) as a determinant of the SREBP pathway. SPRING is a glycosylated Golgi-resident membrane protein and its ablation in Hap1 cells, Hepa1-6 hepatoma cells, and primary murine hepatocytes reduces SREBP signaling. In mice, Spring deletion is embryonic lethal yet silencing of hepatic Spring expression also attenuates the SREBP response. Mechanistically, attenuated SREBP signaling in SPRINGKO cells results from reduced SREBP cleavage-activating protein (SCAP) and its mislocalization to the Golgi irrespective of the cellular sterol status. Consistent with limited functional SCAP in SPRINGKO cells, reintroducing SCAP restores SREBP-dependent signaling and function. Moreover, in line with the role of SREBP in tumor growth, a wide range of tumor cell lines display dependency on SPRING expression. In conclusion, we identify SPRING as a previously unrecognized modulator of SREBP signaling.
Highlights
The sterol-regulatory element binding proteins (SREBP) are central transcriptional regulators of lipid metabolism
Amongst the known core SREBP activating genes, identified as positive regulators of squalene epoxidase (SQLE) expression, we found an uncharacterized gene, C12ORF49, which is further referred to as SREBP-Regulating Gene (SPRING)
The SREBP transcriptional network is a central determinant of homeostatic lipid metabolism
Summary
The sterol-regulatory element binding proteins (SREBP) are central transcriptional regulators of lipid metabolism. Attenuated SREBP signaling in SPRINGKO cells results from reduced SREBP cleavage-activating protein (SCAP) and its mislocalization to the Golgi irrespective of the cellular sterol status. The sterolregulatory element binding proteins (SREBPs) are a family of transcription factors that control all facets of lipid metabolism by regulating the expression of a panel of genes that contain a sterol regulatory element (SRE) in their respective promoter regions[2,3,4]. To identify unknown determinants of the SREBP pathway we applied a set of mammalian haploid genetic screens and report here the identification of the SREBP Regulating Gene SPRING (C12ORF49), as a previously unrecognized factor that governs SREBP activity in mammalian cells and in vivo in mice by controlling the level of functional SCAP
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