Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands.
Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
Nat Commun. 2020 Feb 28;11(1):1128. doi: 10.1038/s41467-020-14811-1.
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 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 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.
固醇调节元件结合蛋白（SREBP）是脂质代谢的核心转录调节因子。我们通过单倍体遗传筛选发现，SREBP 调节基因（SPRING/C12ORF49）是 SREBP 途径的决定因素。SPRING 是一种糖基化的高尔基驻留膜蛋白，其在 Hap1 细胞、Hepa1-6 肝癌细胞和原代小鼠肝细胞中的缺失会降低 SREBP 信号。在小鼠中，Spring 缺失是胚胎致死的，但肝 SPRING 表达的沉默也会减弱 SREBP 反应。从机制上讲，SPRING 细胞中减弱的 SREBP 信号是由于 SREBP 切割激活蛋白（SCAP）减少及其向高尔基体的错误定位所致，而与细胞固醇状态无关。与 SPRING 细胞中有限的功能性 SCAP 一致，重新引入 SCAP 可恢复 SREBP 依赖性信号转导和功能。此外，与 SREBP 在肿瘤生长中的作用一致，广泛的肿瘤细胞系显示依赖于 SPRING 表达。总之，我们发现 SPRING 是 SREBP 信号的一个以前未被识别的调节剂。
