Crucial function of vertebrate glutaredoxin 3 (PICOT) in iron homeostasis and hemoglobin maturation
- Authors
- Haunhorst, P., Hanschmann, E.M., Bräutigam, L., Stehling, O., Hoffmann, B., Mühlenhoff, U., Lill, R., Berndt, C., and Lillig, C.H.
- ID
- ZDB-PUB-130502-15
- Date
- 2013
- Source
- Molecular biology of the cell 24(12): 1895-1903 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Base Sequence
- Carrier Proteins/genetics
- Carrier Proteins/metabolism*
- Embryo, Nonmammalian/embryology
- Embryo, Nonmammalian/metabolism
- Glutaredoxins/genetics
- Glutaredoxins/metabolism
- HeLa Cells
- Hemoglobins/metabolism*
- Homeostasis*
- Humans
- Iron/metabolism*
- Iron Regulatory Protein 1/metabolism
- Iron Regulatory Protein 2/metabolism
- Microscopy, Fluorescence
- Molecular Sequence Data
- RNA Interference
- Sequence Homology, Amino Acid
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 23615448 Full text @ Mol. Biol. Cell
The mechanisms of how eukaryotic cells handle and distribute the essential micronutrient iron within the cytosol and other cellular compartments are only beginning to emerge. The yeast monothiol multidomain glutaredoxins (Grx) 3 and 4 are essential for both transcriptional iron regulation and intracellular iron distribution. Despite the fact that the mechanisms of iron metabolism differ drastically in fungi and higher eukaryotes, the glutaredoxins are conserved, yet their precise function in vertebrates has remained elusive. Here, we demonstrate a crucial role of the vertebrate-specific monothiol multidomain Grx3 (PICOT) in cellular iron homeostasis. During zebrafish embryonic development, depletion of Grx3 severely impaired the maturation of hemoglobin, the major iron-consuming process. Silencing of human Grx3 expression in HeLa cells decreased the activities of several cytosolic Fe/S proteins, for instance iron regulatory protein 1, a major component of posttranscriptional iron regulation. As a consequence, Grx3-depleted cells showed decreased levels of ferritin and increased levels of transferrin receptor, features characteristic of cellular iron starvation. Apparently, Grx3-deficient cells are not able to efficiently utilize iron, despite unimpaired cellular iron uptake. These data suggest an evolutionary conserved role of cytosolic monothiol multidomain glutaredoxins in cellular iron metabolism pathways including the biogenesis of Fe/S proteins and hemoglobin maturation.