Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism

Anke Loregger, Matthijs Raaben, Joppe Nieuwenhuis, Josephine M. E. Tan, Lucas T. Jae, Lisa G. Hengel, Sebastian Hendrix, Marlene Berg, Saskia Scheij, Ji-Ying Song, Ivo J. Huijbers, Lona J. Kroese, Roelof Ottenhoff, Michel Weeghel, Bart Sluis, Thijn Brummelkamp () and Noam Zelcer ()
Additional contact information
Anke Loregger: University of Amsterdam
Matthijs Raaben: The Netherlands Cancer Institute
Joppe Nieuwenhuis: The Netherlands Cancer Institute
Josephine M. E. Tan: University of Amsterdam
Lucas T. Jae: The Netherlands Cancer Institute
Lisa G. Hengel: The Netherlands Cancer Institute
Sebastian Hendrix: University of Amsterdam
Marlene Berg: University of Amsterdam
Saskia Scheij: University of Amsterdam
Ji-Ying Song: The Netherlands Cancer Institute
Ivo J. Huijbers: The Netherlands Cancer Institute
Lona J. Kroese: The Netherlands Cancer Institute
Roelof Ottenhoff: University of Amsterdam
Michel Weeghel: Academic Medical Center of the University of Amsterdam
Bart Sluis: University Medical Center Groningen
Thijn Brummelkamp: The Netherlands Cancer Institute
Noam Zelcer: University of Amsterdam

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract The sterol-regulatory element binding proteins (SREBP) are central transcriptional regulators of lipid metabolism. Using haploid genetic screens we identify the SREBP Regulating 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.

Date: 2020
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DOI: 10.1038/s41467-020-14811-1

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