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

Figure 3

ER stressing iron homeostasis. Iron homeostasis (upper panel). Hepcidin is today thought to be the key regulator of iron homeostasis. Lower hepcidin levels have been seen associated with progression of iron overload in Hereditary Hemochromatosis (HH). HH is intrinsically related to the gene HFE and to a point mutation commonly known as C282Y replacing cysteine by tyrosine at position 282. A high proportion of HH patients are homozygous for the C282Y mutation. ER stress (lower panel). Studies by two separate groups showed in recent years that the C282Y mutation in HFE provoked the activation of the Unfolded Protein Response (UPR) leading the two groups to consider HH a conformational disorder. In addition, some clinical phenotypic heterogeneity reported in HH has been related to variation in levels of mRNA expression of the endoplasmic reticulum (ER)-chaperone calreticulin (CRT). UPR activation has also been shown by separate groups to affect hepcidin gene expression. The intriguing effect of the UPR on cell surface expression of MHC class I may also contribute to the phenotypic heterogeneity of HH through its putative peripheral effect on numbers of circulating CD8⁺ T cells.