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

Author

Listed:
  • 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
    Ludwig-Maximilians-Universität München)

  • 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
    University Medical Center Groningen)

  • Thijn Brummelkamp

    (The Netherlands Cancer Institute
    CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Cancer Genomics Center)

  • Noam Zelcer

    (University of Amsterdam)

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.

Suggested Citation

  • 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. , 2020. "Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14811-1
    DOI: 10.1038/s41467-020-14811-1
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    Cited by:

    1. Sebastian Hendrix & Vincent Dartigue & Hailee Hall & Shrankhla Bawaria & Jenina Kingma & Bilkish Bajaj & Noam Zelcer & Daniel L. Kober, 2024. "SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Sebastian Hendrix & Jenina Kingma & Roelof Ottenhoff & Masoud Valiloo & Monika Svecla & Lobke F. Zijlstra & Vinay Sachdev & Kristina Kovac & Johannes H. M. Levels & Aldo Jongejan & Jan F. Boer & Folke, 2023. "Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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