Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut, USA.
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Traffic. 2023 Jan;24(1):4-19. doi: 10.1111/tra.12873.
The trans-Golgi Network (TGN) sorts molecular "addresses" and sends newly synthesized proteins to their destination via vesicular transport carriers. Despite the functional significance of packaging processes at the TGN, the sorting of soluble proteins remains poorly understood. Recent research has shown that the Golgi resident protein Cab45 is a significant regulator of secretory cargo sorting at the TGN. Cab45 oligomerizes upon transient Ca influx, recruits soluble cargo molecules (clients), and packs them in sphingomyelin-rich transport carriers. However, the identity of client molecules packed into Cab45 vesicles is scarce. Therefore, we used a precise and highly efficient secretome analysis technology called hiSPECs. Intriguingly, we observed that Cab45 deficient cells manifest hypersecretion of lysosomal hydrolases. Specifically, Cab45 deficient cells secrete the unprocessed precursors of prosaposin (PSAP) and progranulin (PGRN). In addition, lysosomes in these cells show an aberrant perinuclear accumulation suggesting a new role of Cab45 in lysosomal positioning. This work uncovers a yet unknown function of Cab45 in regulating lysosomal function.
反式高尔基体网络（TGN）对分子“地址”进行分类，并通过囊泡运输载体将新合成的蛋白质发送到其目的地。尽管 TGN 处的包装过程具有功能意义，但可溶性蛋白质的分类仍知之甚少。最近的研究表明，高尔基体驻留蛋白 Cab45 是 TGN 处分泌货物分类的重要调节剂。Cab45 在短暂的 Ca 流入时寡聚化，招募可溶性货物分子（客户），并将它们包装在富含神经鞘磷脂的运输载体中。然而，包装在 Cab45 囊泡中的客户分子的身份却很少。因此，我们使用了一种称为 hiSPECs 的精确且高效的分泌组分析技术。有趣的是，我们观察到 Cab45 缺陷细胞表现出溶酶体水解酶的过度分泌。具体而言，Cab45 缺陷细胞分泌前蛋白聚糖（PSAP）和颗粒蛋白前体（PGRN）的未加工前体。此外，这些细胞中的溶酶体显示出异常的核周聚集，表明 Cab45 在溶酶体定位方面具有新的作用。这项工作揭示了 Cab45 在调节溶酶体功能方面的一个未知功能。
