Grab regulates transferrin receptor recycling and iron uptake in developing erythroblasts

Abstract

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.

Endothelial transferrin receptor 1 contributes to thrombogenesis through cascade ferroptosis

“…First, we hypothesized that this unequal iron distribution may be caused by the high expression of TFRC. TFRC encodes TFR1, which is a membrane protein that regulates iron intake, has affinity for transferrin bound to Fe 3+ ions and is the most crucial method for importing iron [ 32 , 33 ]. The tissue iron level was reduced after the expression of TFRC was knocked down, which could explain the iron overload in tissues.…”