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Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism by Loregger, Anke; Raaben, Matthijs; Nieuwenhuis, Joppe; Tan, Josephine M. E.; Jae, Lucas T.; van den Hengel, Lisa G.; Hendrix, Sebastian; van den Berg, Marlene; Scheij, Saskia; Song, Ji-Ying; Huijbers, Ivo J.; Kroese, Lona J.; Ottenhoff, Roelof; van Weeghel, Michel; van de Sluis, Bart; Brummelkamp, Thijn; Zelcer, Noam is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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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 SPRING^KO^ 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 SPRING^KO^ 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.

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Author

Loregger, Anke; Raaben, Matthijs; Nieuwenhuis, Joppe; Tan, Josephine M. E.; Jae, Lucas T.; van den Hengel, Lisa G.; Hendrix, Sebastian; van den Berg, Marlene; Scheij, Saskia; Song, Ji-Ying; Huijbers, Ivo J.; Kroese, Lona J.; Ottenhoff, Roelof; van Weeghel, Michel; van de Sluis, Bart; Brummelkamp, Thijn; Zelcer, Noam

Publisher

Nature Publishing Group; Springer Science and Business Media LLC; [London]: Nature Publishing Group, 2010-; Society for Mining, Metallurgy and Exploration Inc.; Research Square (ISSN 2041-1723)

Published

2020

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)