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

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.

CHOP Silencing Reduces Acute Brain Injury in the Rat Model of Subarachnoid Hemorrhage

“…This effect can be mediated by ischemic stimulation 12 but also by the action of hemoglobin degradation products including iron 13 . Previous studies revealed that CHOP mediates apoptosis after cerebral ischemia 14 .…”

Interstrain differences in the progression of nonalcoholic steatohepatitis to fibrosis in mice are associated with altered hepatic iron metabolism

“…For instance, it has been shown that alterations in iron homeostasis can affect the fatty acid metabolism [21] and apolipoprotein B secretion [28], contributing to lipid metabolism abnormalities and intracellular lipid accumulation in the liver. Additionally, it has been demonstrated that aberrant iron metabolism contributes to insulin resistance [29], inflammation [30] and the induction of oxidative and endoplasmic reticulum stress [13,17], key events in the pathogenesis of NAFLD. Among these processes, the effect of aberrant iron metabolism on the progression of NAFLD to its advanced states, especially fibrogenesis [11,31,32], may be the most significant.…”

“…Several lines of evidence have indicated a tight interaction between lipid and one-carbon metabolism, the induction of oxidative and endoplasmic reticulum stress and hepatic iron homeostasis in the molecular pathogenesis of both alcoholic and nonalcoholic liver injury [16][17][18][19]. Importantly, it has been demonstrated that steatosis, inflammation and other NAFLD-related molecular abnormalities are attenuated as NAFLD progresses or after removal of the causative factor, while the peculiarities in iron-related metabolism are exacerbated [20,21].…”

Role of hepcidin and its downstream proteins in early brain injury after experimental subarachnoid hemorrhage in rats

“…C/EBPa inhibits the expression of other members of C/EBP family, and CHOP exhausts this inhibition and enhances the expression of hepcidin [5,6]; we suspect that the up-regulated expression of hepcidin exacerbates apoptosis. Hepcidin regulates cellular iron efflux by inducing internalization of ferroportin-1 (Fpn1) [7].…”