Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell Chem Biol. 2021 Feb 18;28(2):169-179.e7. doi: 10.1016/j.chembiol.2020.10.003. Epub 2020 Oct 22.
Sterol regulatory element-binding proteins (SREBPs) are master transcriptional regulators of the mevalonate pathway and lipid metabolism and represent an attractive therapeutic target for lipid metabolic disorders. SREBPs are maintained in the endoplasmic reticulum (ER) in a tripartite complex with SREBP cleavage-activating protein (SCAP) and insulin-induced gene protein (INSIG). When new lipid synthesis is required, the SCAP-SREBP complex dissociates from INSIG and undergoes ER-to-Golgi transport where the N-terminal transcription factor domain is released by proteolysis. The mature transcription factor translocates to the nucleus and stimulates expression of the SREBP gene program. Previous studies showed that dipyridamole, a clinically prescribed phosphodiesterase (PDE) inhibitor, potentiated statin-induced tumor growth inhibition. Dipyridamole limited nuclear accumulation of SREBP, but the mechanism was not well resolved. In this study, we show that dipyridamole selectively blocks ER-to-Golgi movement of the SCAP-SREBP complex and that this is independent of its PDE inhibitory activity.
固醇调节元件结合蛋白（SREBPs）是甲羟戊酸途径和脂质代谢的主要转录调节因子，是脂质代谢紊乱的一个有吸引力的治疗靶点。SREBPs 与 SREBP 切割激活蛋白（SCAP）和胰岛素诱导基因蛋白（INSIG）形成三联复合物，保持在内质网（ER）中。当需要新的脂质合成时，SCAP-SREBP 复合物与 INSIG 分离，并通过内质网-高尔基体运输，其中 N 端转录因子结构域通过蛋白水解释放。成熟的转录因子易位到细胞核，并刺激 SREBP 基因程序的表达。先前的研究表明，临床处方的磷酸二酯酶（PDE）抑制剂双嘧达莫增强了他汀类药物诱导的肿瘤生长抑制作用。双嘧达莫限制了 SREBP 的核积累，但机制尚不清楚。在这项研究中，我们表明双嘧达莫选择性地阻断了 SCAP-SREBP 复合物的内质网-高尔基体运动，而这与其 PDE 抑制活性无关。
