Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences and Gastroenterology and Metabolism, University of Amsterdam, Meibergdreef 15, Amsterdam, the Netherlands.
Curr Opin Lipidol. 2023 Oct 1;34(5):201-207. doi: 10.1097/MOL.0000000000000894. Epub 2023 Aug 3.
The SREBP transcription factors are master regulators of lipid homeostasis owing to their role in controlling cholesterol and fatty acid metabolism. The core machinery required to promote their trafficking and proteolytic activation has been established close to 20 years ago. In this review, we summarize the current understanding of a newly identified regulator of SREBP signaling, SPRING (formerly C12ORF49), its proposed mechanism of action, and its role in lipid metabolism.
Using whole-genome functional genetic screens we, and others, have recently identified SPRING as a novel regulator of SREBP signaling. SPRING is a Golgi-resident single-pass transmembrane protein that is required for proteolytic activation of SREBPs in this compartment. Mechanistic studies identified regulation of S1P, the protease that cleaves SREBPs, and control of retrograde trafficking of the SREBP chaperone SCAP from the Golgi to the ER as processes requiring SPRING. Emerging studies suggest an important role for SPRING in regulating circulating and hepatic lipid levels in mice and potentially in humans.
Current studies support the notion that SPRING is a novel component of the core SREBP-activating machinery. Additional studies are warranted to elucidate its role in cellular and systemic lipid metabolism.
SREBP 转录因子是脂质稳态的主要调节因子，因为它们在控制胆固醇和脂肪酸代谢中发挥作用。近 20 年前，就已经建立了促进其运输和蛋白水解激活所需的核心机制。在这篇综述中，我们总结了一种新发现的 SREBP 信号通路调节剂 SPRING（以前称为 C12ORF49）的最新认识，其作用机制及其在脂质代谢中的作用。
利用全基因组功能遗传筛选，我们和其他人最近发现 SPRING 是 SREBP 信号的一种新型调节剂。SPRING 是一种驻留在高尔基体内的单次跨膜蛋白，在高尔基体内是 SREBPs 蛋白水解激活所必需的。机制研究鉴定了 S1P 的调节，S1P 是切割 SREBPs 的蛋白酶，以及控制 SREBP 伴侣 SCAP 从高尔基体到内质网的逆行运输，这些过程都需要 SPRING。新兴研究表明，SPRING 在调节小鼠和潜在人类的循环和肝脏脂质水平方面具有重要作用。
目前的研究支持 SPRING 是核心 SREBP 激活机制的新组成部分的观点。需要进一步的研究来阐明其在细胞和全身脂质代谢中的作用。
