Doyle Colleen P, Timple Liz, Hammond Gerald R V
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Contact (Thousand Oaks). 2024 Feb 22;7:25152564241232196. doi: 10.1177/25152564241232196. eCollection 2024 Jan-Dec.
The lipid phosphatidylinositol 4-phosphate (PI4P) plays a master regulatory role at Golgi membranes, orchestrating membrane budding, non-vesicular lipid transport and membrane organization. It follows that harmonious Golgi function requires strictly maintained PI4P homeostasis. One of the most abundant PI4P effector proteins is the oxysterol binding protein (OSBP), a lipid transfer protein that exchanges trans-Golgi PI4P for ER cholesterol. Although this protein consumes PI4P as part of its lipid anti-porter function, whether it actively contributes to Golgi PI4P homeostasis has been questioned. Here, we employed a series of acute and chronic genetic manipulations, together with orthogonal targeting of OSBP, to interrogate its control over Golgi PI4P abundance. Modulating OSBP levels at ER:Golgi membrane contact sites produces reciprocal changes in PI4P levels. Additionally, we observe that OSBP has a high capacity for PI4P turnover, even at orthogonal organelle membranes. However, despite also visiting the plasma membrane, endogenous OSBP makes no impact on PI4P levels in this compartment. We conclude that OSBP is a major determinant of Golgi PI4P homeostasis.
脂质磷脂酰肌醇4-磷酸（PI4P）在高尔基体膜上发挥着主要调节作用，协调膜出芽、非囊泡脂质转运和膜组织。因此，高尔基体的和谐功能需要严格维持PI4P的稳态。最丰富的PI4P效应蛋白之一是氧化甾醇结合蛋白（OSBP），它是一种脂质转运蛋白，可将反式高尔基体PI4P与内质网胆固醇进行交换。尽管该蛋白作为其脂质反向转运功能的一部分消耗PI4P，但它是否积极参与高尔基体PI4P稳态一直受到质疑。在这里，我们采用了一系列急性和慢性基因操作，以及对OSBP的正交靶向，来探究其对高尔基体PI4P丰度的控制。在内质网与高尔基体膜接触位点调节OSBP水平会使PI4P水平产生相反的变化。此外，我们观察到OSBP即使在正交细胞器膜上也具有很高的PI4P周转能力。然而，尽管内源性OSBP也会作用于质膜，但它对该区域的PI4P水平没有影响。我们得出结论，OSBP是高尔基体PI4P稳态的主要决定因素。
