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. van den Hengel, Sebastian Hendrix, Marlene van den Berg, Saskia Scheij, Ji-Ying Song, Ivo J. Huijbers, Lona J. Kroese, Roelof Ottenhoff, Michel van Weeghel, Bart van de Sluis, Thijn Brummelkamp*, Noam Zelcer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 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.

Original languageEnglish
Article number1128
Number of pages14
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 28-Feb-2020

Keywords

  • ACTIVATING PROTEIN SCAP
  • LEUCINE ZIPPER PROTEIN
  • VIRUS ENTRY REQUIRES
  • ENDOPLASMIC-RETICULUM
  • SQUALENE MONOOXYGENASE
  • FEEDBACK-REGULATION
  • STEROL SYNTHESIS
  • BINDING
  • CLEAVAGE
  • RECEPTOR

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