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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 β (2)-microglobulin (β (2)m) and the cell surface expression of the protein: with two majo...
Autores principales: | , , |
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Formato: | Texto |
Lenguaje: | English |
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Hindawi Publishing Corporation
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010616/ https://www.ncbi.nlm.nih.gov/pubmed/21197476 http://dx.doi.org/10.1155/2011/896474 |
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author | Oliveira, Susana J. de Sousa, Maria Pinto, Jorge P. |
author_facet | Oliveira, Susana J. de Sousa, Maria Pinto, Jorge P. |
author_sort | Oliveira, Susana J. |
collection | PubMed |
description | 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 β (2)-microglobulin (β (2)m) 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 β (2)m, 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. |
format | Text |
id | pubmed-3010616 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Hindawi Publishing Corporation |
record_format | MEDLINE/PubMed |
spelling | pubmed-30106162010-12-30 ER Stress and Iron Homeostasis: A New Frontier for the UPR Oliveira, Susana J. de Sousa, Maria Pinto, Jorge P. Biochem Res Int Review Article 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 β (2)-microglobulin (β (2)m) 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 β (2)m, 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. Hindawi Publishing Corporation 2011 2010-12-20 /pmc/articles/PMC3010616/ /pubmed/21197476 http://dx.doi.org/10.1155/2011/896474 Text en Copyright © 2011 Susana J. Oliveira et al. https://creativecommons.org/licenses/by/3.0/ 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. |
spellingShingle | Review Article Oliveira, Susana J. de Sousa, Maria Pinto, Jorge P. ER Stress and Iron Homeostasis: A New Frontier for the UPR |
title | ER Stress and Iron Homeostasis: A New Frontier for the UPR |
title_full | ER Stress and Iron Homeostasis: A New Frontier for the UPR |
title_fullStr | ER Stress and Iron Homeostasis: A New Frontier for the UPR |
title_full_unstemmed | ER Stress and Iron Homeostasis: A New Frontier for the UPR |
title_short | ER Stress and Iron Homeostasis: A New Frontier for the UPR |
title_sort | er stress and iron homeostasis: a new frontier for the upr |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010616/ https://www.ncbi.nlm.nih.gov/pubmed/21197476 http://dx.doi.org/10.1155/2011/896474 |
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