ER Stress and Iron Homeostasis: A New Frontier for the UPR
The C282Y mutation of HFE accounts for the majority of cases of the iron overload disease Hereditary Hemochromatosis (HH). The conformational changes introduced by this mutation impair the HFE association with β2-microglobulin (β2m) and the cell surface expressi...
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| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2011-01-01
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| Series: | Biochemistry Research International |
| Online Access: | http://dx.doi.org/10.1155/2011/896474 |
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| Summary: | The C282Y mutation of HFE accounts for the majority of cases of the iron overload disease Hereditary Hemochromatosis (HH).
The conformational changes introduced by this mutation impair the HFE association with β2-microglobulin
(β2m) and the cell surface expression of the protein: with two major consequences. From a functional perspective,
the ability of HFE to bind to transferrin receptors 1 and 2 is lost in the C282Y mutant, thus affecting hepcidin regulation. Also due to the faulty
assembly with β2m, HFE-C282Y molecules remain in the endoplasmic reticulum (ER) as aggregates that undergo
proteasomal degradation and activate an Unfolded Protein Response (UPR). UPR activation, regardless of the ER stress stimuli, was shown
to reshape the expression profile of iron-related genes and to decrease MHC-I cell surface expression. The possibility of a HFE-C282Y-mediated
interplay between the UPR and iron homeostasis influencing disease progression and the clinical heterogeneity among C282Y carriers is
discussed. The responsiveness of the ER chaperone calreticulin to both ER and iron-induced oxidative stresses, and its correlation with HH
patients’ phenotype, reinforce the interest of dissecting the UPR signaling/iron metabolism crosstalk and points to the potential
clinical value of use of pharmacological chaperones in HFE-HH. |
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| ISSN: | 2090-2247 2090-2255 |