TY - JOUR
T1 - Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism
AU - Loregger, Anke
AU - Raaben, Matthijs
AU - Nieuwenhuis, Joppe
AU - Tan, Josephine M. E.
AU - Jae, Lucas T.
AU - van den Hengel, Lisa G.
AU - Hendrix, Sebastian
AU - van den Berg, Marlene
AU - Scheij, Saskia
AU - Song, Ji-Ying
AU - Huijbers, Ivo J.
AU - Kroese, Lona J.
AU - Ottenhoff, Roelof
AU - van Weeghel, Michel
AU - van de Sluis, Bart
AU - Brummelkamp, Thijn
AU - Zelcer, Noam
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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 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.
AB - 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 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.
UR - http://www.scopus.com/inward/record.url?scp=85081018271&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-020-14811-1
DO - https://doi.org/10.1038/s41467-020-14811-1
M3 - Article
C2 - 32111832
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1128
ER -