Phosphatidylinositol 4-monophosphate [PtdIns(4)P] is a precursor for various phosphoinositides but also a membrane-embedded component crucial for membrane contact sites (MCSs). Several lipid transfer proteins are recruited to MCSs by recognizing PtdIns(4)P; however, it remains poorly elucidated how the production of PtdIns(4)P for lipid transport at MCSs is regulated. Following human genome-wide screening, we discovered that the PtdIns(4)P-related genes PI4KB, ACBD3, and C10orf76 are involved in endoplasmic reticulum-to-Golgi trafficking of ceramide by the ceramide transport protein CERT. CERT preferentially utilizes PtdIns(4)P generated by PI4KB recruited to the Golgi by C10orf76 rather than by ACBD3. Super-resolution microscopy observation revealed that C10orf76 predominantly localizes at distal Golgi regions, where sphingomyelin (SM) synthesis primarily occurs, while the majority of ACBD3 localizes at more proximal regions. This study provides a proof-of-concept that distinct pools of PtdIns(4)P are generated in different subregions, even within the same organelle, to facilitate interorganelle metabolic channeling for the ceramide-to-SM conversion.

中文翻译：

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C10orf76-PI4KB 轴协调 CERT 介导的神经酰胺运输至远端高尔基体

磷脂酰肌醇 4-单磷酸 [PtdIns(4)P] 是各种磷酸肌醇的前体，也是对膜接触位点 (MCS) 至关重要的膜嵌入成分。一些脂质转移蛋白通过识别 PtdIns(4)P 被招募到 MCS；然而，目前尚不清楚如何调节 MCS 脂质运输的 PtdIns(4)P 的产生。经过人类全基因组筛选，我们发现 PtdIns(4)P 相关基因 PI4KB、ACBD3 和 C10orf76 通过神经酰胺转运蛋白 CERT 参与神经酰胺从内质网到高尔基体的运输。CERT 优先利用由 C10orf76 而不是 ACBD3 招募到高尔基体的 PI4KB 生成的 PtdIns(4)P。超分辨率显微镜观察显示，C10orf76 主要位于远端高尔基体区域，鞘磷脂 (SM) 合成主要发生在该区域，而大多数 ACBD3 位于更近端的区域。这项研究提供了一个概念验证，即在不同的亚区域，甚至在同一细胞器内，都会产生不同的 PtdIns(4)P 池，以促进神经酰胺向 SM 转化的细胞器间代谢通道。