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

Nat Commun. 2020 Feb 28;11(1):1128. doi: 10.1038/s41467-020-14811-1.

Anke Loregger ^# ¹, Matthijs Raaben ^# ², Joppe Nieuwenhuis ^# ², Josephine M E Tan ¹, Lucas T Jae ² ³, Lisa G van den Hengel ², Sebastian Hendrix ¹, Marlene van den Berg ¹, Saskia Scheij ¹, Ji-Ying Song ⁴, Ivo J Huijbers ⁵, Lona J Kroese ⁵, Roelof Ottenhoff ¹, Michel van Weeghel ⁶, Bart van de Sluis ⁷ ⁸, Thijn Brummelkamp ⁹ ¹⁰ ¹¹, Noam Zelcer ¹²

Affiliations

1 Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.
2 Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
3 Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor Lynen-Str. 25, 81377, Munich, Germany.
4 Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
5 Mouse Clinic for Cancer and Aging (MCCA) Transgenic Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
6 Laboratory of Genetic and Metabolic Diseases and Core Facility Metabolomics, Academic Medical Center of the University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.
7 Department of Pediatrics, University Medical Center Groningen, Antonius Deusinglaan 1, 9713AV, Groningen, The Netherlands.
8 iPSC/CRISPR Center Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713AV, Groningen, The Netherlands.
9 Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. [email protected].
10 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, A-1090, Vienna, Austria. [email protected].
11 Cancer Genomics Center, Amsterdam, The Netherlands. [email protected].
12 Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands. [email protected].
# Contributed equally.

PMID: 32111832 DOI: 10.1038/s41467-020-14811-1

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 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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