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  • Title: Evidence for dimerization of ferroportin in a human hepatic cell line using proximity ligation assays.
    Author: Rishi G, Secondes ES, Wallace DF, Subramaniam VN.
    Journal: Biosci Rep; 2020 May 29; 40(5):. PubMed ID: 32301493.
    Abstract:
    Mutations in the only known iron exporter ferroportin (FPN) in humans are associated with the autosomal dominantly inherited iron overload disorder ferroportin disease or type IV hereditary hemochromatosis (HH). While our knowledge of the central role of FPN in iron homeostasis has grown in the last 20 years, there exist some questions surrounding the structure and membrane topology of FPN with conflicting data on whether this receptor acts as a monomer or a multimer. To investigate and determine if FPN dimerization occurs in cells, we used novel tools including a variety of different FPN constructs expressing different tagged versions of the protein, a novel antibody that only detects cell surface FPN and proximity ligation assays. The results of the present study suggest that both the carboxy- and amino-termini of the FPN protein are intracellular. We also show that exogenously transfected FPN forms dimers; these dimers can be formed between the wild-type and mutant FPN proteins. This is the first study to examine the intracellular dimerization of FPN protein. Using proximity ligation assays, we show intracellular localization of FPN dimers and the interaction between FPN and hepcidin proteins as well. These results have important implications in the field of iron metabolism and add to our knowledge about FPN membrane topology and physiology of iron transport. This will be of importance in understanding the clinical implications of FPN mutations and of interest to future research aimed at targeting FPN expression to modulate iron homeostasis.
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