Grab regulates transferrin receptor recycling and iron uptake in developing erythroblasts
Grab regulates transferrin receptor recycling and iron uptake in developing erythroblasts
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Grab 调节转铁蛋白受体的再循环和发育中的成红细胞的铁吸收。
DOI：
10.1182/blood.2021015189
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发表时间：
2022-09-08
期刊：
影响因子：
20.3
通讯作者：
Chen, Caiyong
中科院分区：
文献类型：
--
作者：
Chen, Mengying;Zhang, Yuhan;Chen, Caiyong
发育中的红细胞通过转铁蛋白(Tf)循环获得大量的铁，该循环涉及Tf-Tf受体(Tfrc)复合体的内吞、分选和循环。以前对血红蛋白缺乏症(HBD)小鼠的研究表明，胞囊复合体对于Tfrc的循环是必不可少的；然而，红细胞高效地胞吐和循环Tfrc的确切机制尚不清楚。在这里，我们确定鸟嘌呤核苷酸交换因子GRAB是红血球生成过程中转铁蛋白循环和铁代谢的关键调节因子。GRAB在分化的红细胞中高表达。Grab的缺失降低了Tfrc的循环和铁的摄取，导致小鼠原始红细胞、哺乳动物红细胞白血病细胞和斑马鱼胚胎的血红素化缺陷。这些缺陷可以通过补充铁和Hinokitiol一起缓解，Hinokitiol是一种小分子天然化合物，可以独立于转铁蛋白循环介导铁的运输。从机制上讲，Grab通过激活GTP酶Rab8来调节Tfrc相关囊泡的胞吐，进而促进胞外复合体的募集和囊泡的胞吐。我们的结果揭示了GRAB在调节转铁蛋白循环中的关键作用，并为铁稳态和红细胞生成提供了新的见解。
Developing erythroblasts acquire massive amounts of iron through the transferrin (Tf) cycle, which involves endocytosis, sorting, and recycling of the Tf-Tf receptor (Tfrc) complex. Previous studies on the hemoglobin-deficit (hbd) mouse have shown that the exocyst complex is indispensable for the Tfrc recycling; however, the precise mechanism underlying the efficient exocytosis and recycling of Tfrc in erythroblasts remains unclear. Here, we identify the guanine nucleotide exchange factor Grab as a critical regulator of the Tf cycle and iron metabolism during erythropoiesis. Grab is highly expressed in differentiating erythroblasts. Loss of Grab diminishes the Tfrc recycling and iron uptake, leading to hemoglobinization defects in mouse primary erythroblasts, mammalian erythroleukemia cells, and zebrafish embryos. These defects can be alleviated by supplementing iron together with hinokitiol, a small-molecule natural compound that can mediate iron transport independent of the Tf cycle. Mechanistically, Grab regulates the exocytosis of Tfrc-associated vesicles by activating the GTPase Rab8, which subsequently promotes the recruitment of the exocyst complex and vesicle exocytosis. Our results reveal a critical role for Grab in regulating the Tf cycle and provide new insights into iron homeostasis and erythropoiesis.