School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
University of Chinese Academy of Sciences, Beijing 101408, China.
Cells. 2023 Apr 4;12(7):1079. doi: 10.3390/cells12071079.
KDEL receptor-1 maintains homeostasis in the early secretory pathway by capturing and retrieving ER chaperones to the ER during heavy secretory activity. Unexpectedly, a fraction of the receptor is also known to reside in the plasma membrane (PM), although it is largely unknown exactly how the KDEL receptor gets exported from the Golgi and travels to the PM. We have previously shown that a Golgi scaffolding protein (ACBD3) facilitates KDEL receptor localization at the Golgi via the regulating cargo wave-induced cAMP/PKA-dependent signaling pathway. Upon endocytosis, surface-expressed KDEL receptor undergoes highly complex itineraries through the Golgi and the endo-lysosomal compartments, where the endocytosed receptor utilizes Rab14A- and Rab11A-positive recycling endosomes and clathrin-decorated tubulovesicular carriers. In this study, we sought to investigate the mechanism through which the KDEL receptor gets exported from the Golgi en route to the PM. We report here that ACBD3 depletion results in greatly increased trafficking of KDEL receptor to the PM via Rab4A-positive tubular carriers emanating from the Golgi. Expression of constitutively activated Rab4A mutant (Q72L) increases the surface expression of KDEL receptor up to 2~3-fold, whereas Rab4A knockdown or the expression of GDP-locked Rab4A mutant (S27N) inhibits KDEL receptor targeting of the PM. Importantly, KDELR trafficking from the Golgi to the PM is independent of PKA- and Src kinase-mediated mechanisms. Taken together, these results reveal that ACBD3 and Rab4A play a key role in regulating KDEL receptor trafficking to the cell surface.
KDEL 受体-1 在早期分泌途径中通过在大量分泌活动期间捕获和将 ER 伴侣蛋白返回到 ER 中来维持内环境平衡。出乎意料的是，受体的一部分也已知存在于质膜 (PM) 中，尽管确切的 KDEL 受体如何从高尔基体中输出并转移到 PM 中还很大程度上未知。我们之前已经表明，一种高尔基体支架蛋白 (ACBD3) 通过调节货物波诱导的 cAMP/PKA 依赖性信号通路促进 KDEL 受体在高尔基体中的定位。在胞吞作用后，表面表达的 KDEL 受体通过高尔基体和内体溶酶体隔室经历高度复杂的途径，其中内吞的受体利用 Rab14A- 和 Rab11A 阳性再循环内体和网格蛋白包被的小管泡状载体。在这项研究中，我们试图研究 KDEL 受体从高尔基体输出到 PM 的机制。我们在这里报告，ACBD3 耗竭导致通过从高尔基体发出的 Rab4A 阳性管状载体将 KDEL 受体大量转运到 PM。组成型激活 Rab4A 突变体 (Q72L) 的表达将 KDEL 受体的表面表达增加高达 2-3 倍，而 Rab4A 敲低或 GDP 锁定 Rab4A 突变体 (S27N) 的表达抑制 KDEL 受体靶向 PM。重要的是，KDELR 从高尔基体到 PM 的运输不依赖于 PKA 和 Src 激酶介导的机制。总之，这些结果表明，ACBD3 和 Rab4A 在调节 KDEL 受体向细胞表面的运输中发挥关键作用。
