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Biochemistry Research International
Volume 2011, Article ID 896474, 10 pages
Review Article

ER Stress and Iron Homeostasis: A New Frontier for the UPR

1Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal
2Instituto de Ciências Biomédicas Abel Salazar, Largo Prof. Abel Salazar 2, 4099-003 Porto, Portugal

Received 12 July 2010; Accepted 1 October 2010

Academic Editor: Emil Pai

Copyright © 2011 Susana J. Oliveira et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.