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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3915-3921
HFE Downregulates Iron Uptake From Transferrin and Induces
Iron-Regulatory Protein Activity in Stably Transfected Cells
H.D. Riedel,
M.U. Muckenthaler,
S.G. Gehrke,
I. Mohr,
K. Brennan,
T. Herrmann,
B.A. Fitscher,
M.W. Hentze, and
W. Stremmel
From the Department of Medicine, University Hospital of Heidelberg;
and the European Molecular Biology Lab (EMBL), Heidelberg, Germany.
Hereditary hemochromatosis (HH) is a common autosomal-recessive
disorder of iron metabolism. More than 80% of HH patients are
homozygous for a point mutation in a major histocompatibility complex
(MHC) class I type protein (HFE), which results in a lack of HFE
expression on the cell surface. A previously identified interaction of
HFE and the transferrin receptor suggests a possible regulatory role of
HFE in cellular iron absorption. Using an HeLa cell line stably
transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron
uptake. We demonstrate that the overproduction of HFE results in
decreased iron uptake from diferric transferrin. Moreover, HFE
expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can
affect the intracellular "labile iron pool." The increase in IRP
activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels.
These findings are discussed in the context of the pathophysiology of
HH and a possible role of iron-responsive element (IRE)-containing mRNAs.
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