MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, 510632, China.
Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, China.
Nat Commun. 2022 Jul 29;13(1):4390. doi: 10.1038/s41467-022-32104-7.
Lipid remodeling is crucial for malignant cell transformation and tumorigenesis, but the precise molecular processes involved and direct evidences for these in vivo remain elusive. Here, we report that oxysterol-binding protein (OSBP)-related protein 4 L (ORP4L) is expressed in adult T-cell leukemia (ATL) cells but not normal T-cells. In ORP4L knock-in T-cells, ORP4L dimerizes with OSBP to control the shuttling of OSBP between the Golgi apparatus and the plasma membrane (PM) as an exchanger of phosphatidylinositol 4-phosphate [PI(4)P]/cholesterol. The PI(4)P arriving at the PM via this transport machinery replenishes phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] and phosphatidylinositol (3,4,5) trisphosphate [PI(3,4,5)P] biosynthesis, thus contributing to PI3K/AKT hyperactivation and T-cell deterioration in vitro and in vivo. Disruption of ORP4L and OSBP dimerization disables PI(4)P transport and T-cell leukemogenesis. In summary, we identify a non-vesicular lipid transport machinery between Golgi and PM maintaining the oncogenic signaling competence initiating T-cell deterioration and leukemogenesis.
脂质重塑对于恶性细胞转化和肿瘤发生至关重要，但涉及的精确分子过程以及这些过程在体内的直接证据仍然难以捉摸。在这里，我们报告了甾醇结合蛋白（OSBP）相关蛋白 4L（ORP4L）在成人 T 细胞白血病（ATL）细胞中表达，但在正常 T 细胞中不表达。在 ORP4L 敲入 T 细胞中，ORP4L 与 OSBP 二聚化，控制 OSBP 在高尔基器和质膜（PM）之间穿梭，作为磷酸肌醇 4-磷酸[PI（4）P]/胆固醇的交换器。通过这种运输机制到达 PM 的 PI（4）P 补充了磷脂酰肌醇 4,5-二磷酸[PI（4,5）P]和磷脂酰肌醇（3,4,5）三磷酸[PI（3,4,5）P]的生物合成，从而有助于体外和体内的 PI3K/AKT 过度激活和 T 细胞恶化。ORP4L 和 OSBP 二聚化的破坏使 PI（4）P 转运和 T 细胞白血病发生失能。总之，我们鉴定了一种在高尔基器和 PM 之间维持致癌信号能力的非囊泡脂质转运机制，该机制起始 T 细胞恶化和白血病发生。
