Abstract
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 2m) 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 2m, 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.
Highlights
Occupying a central position in the secretory route, the endoplasmic reticulum (ER) performs a vast array of functions that includes the biosynthesis, folding, assembly, and posttranslational modification of secretory and membranetargeted proteins [1]
The realization that there is a functional intersection between ER stress and iron metabolism emerged first from studies of the genetic disorder of iron overload, Hereditary Hemochromatosis (HH) type 1
By exposing a hepatocyte-derived cell line to chemical agents impairing disulphide bond formation in ER client proteins, we recently demonstrated that ongoing ER stress significantly reshapes the expression profile of iron-related genes, namely, hepcidin, ferroportin, and ferritin H
Summary
Occupying a central position in the secretory route, the endoplasmic reticulum (ER) performs a vast array of functions that includes the biosynthesis, folding, assembly, and posttranslational modification of secretory and membranetargeted proteins [1]. The accuracy of this variety of processes relies on specialized luminal conditions, thoroughly maintained by stringent quality control mechanisms [2]. Arising from a defective regulation of iron absorption, HH is intrinsically related to the gene HFE [4] The product of this gene shares structural homology to a major histocompatibility complex class I (MHC-I) protein, requiring association with β2microglobulin (β2m) for cell surface expression [5, 6]. In light of the recent findings, the Unfolded Protein Response (UPR) has emerged as a promising candidate
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