PUBLICATION

Grab regulates transferrin receptor recycling and iron uptake in developing erythroblasts

Authors
Chen, M., Zhang, Y., Jiang, K., Wang, W., Feng, H., Zhen, R., Moo, C., Zhang, Z., Shi, J., Chen, C.
ID
ZDB-PUB-220714-2
Date
2022
Source
Blood   140(10): 1145-1155 (Journal)
Registered Authors
Chen, Caiyong, Chen, Mengying, Jiang, Kailun, Zhang, Yuhan
Keywords
none
MeSH Terms
  • Receptors, Transferrin*/genetics
  • Receptors, Transferrin*/metabolism
  • Transferrin/metabolism
  • Mammals/metabolism
  • Iron*/metabolism
  • Zebrafish/metabolism
  • Animals
  • Erythroblasts*/metabolism
  • Guanine Nucleotide Exchange Factors*/metabolism
  • Mice
(all 10)
PubMed
35820059 Full text @ Blood
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.
Genes / Markers
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Expression
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Phenotype
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cz3325TgTransgenic Insertion
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    Human Disease / Model
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    Sequence Targeting Reagents
    Target Reagent Reagent Type
    rab3il1MO1-rab3il1MRPHLNO
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    Fish
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    Antibodies
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    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
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    Mapping
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    Citation
    Chen, M., Zhang, Y., Jiang, K., Wang, W., Feng, H., Zhen, R., Moo, C., Zhang, Z., Shi, J., Chen, C. (2022) Grab regulates transferrin receptor recycling and iron uptake in developing erythroblasts. Blood. 140(10):1145-1155.