ER Stress-Inducible Factor CHOP Affects the Expression of Hepcidin by Modulating C/EBPalpha Activity

Oliveira, Sofia Castro; Pinto, Jorge P.; Picarote, Gonçalo; Costa, Vera Marisa; Carvalho, Félix; Rangel, Maria; Sousa, Maria de; Almeida, Sérgio Fernandes de

doi:10.1371/journal.pone.0006618

Cited by 90 publications

(86 citation statements)

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“…38,39 Using 2 separate methods we were unable to detect ER stress in any of the HFE overexpressing animals, including animals overexpressing an ortholog of the common C282Y human missense mutation that has been shown to induce ER stress in cell culture. 40 It is possible that there is acute stress early in the development of the mice, but that cellular adaptations to chronic overexpression of proteins occur over time.…”

Section: Discussionmentioning

confidence: 92%

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Schmidt

Andrews

Fleming

2010

Blood

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Mutations in HFE cause the most common form of hereditary hemochromatosis (HH). We previously showed that liverspecific, transgenic overexpression of murine Hfe stimulates production of the iron regulatory hormone hepcidin. Here, we developed several additional transgenic mouse strains to further interrogate the structural basis of HFE function in the pathophysiology of HH. We hypothesized that the small, cytoplasmic domain of HFE might be necessary for HFE-mediated induction of hepcidin. We demonstrate that, like the full-length protein, overexpression of Hfe proteins lacking the cytoplasmic domain leads to hepcidin induction, iron deficiency and a hypochromic, microcytic anemia. However, high-level expression of a liver-specific Hfe transgene carrying the mouse equivalent of the common HFE C282Y human diseasecausing mutation (murine C294Y ) IntroductionThe common iron overload disease hereditary hemochromatosis (HH) is caused by a chronic increase in dietary iron absorption. A unifying model has emerged to explain the pathogenesis of genetically distinct forms of HH. 1 Aberrant iron homeostasis results from interruption of a regulatory axis involving the hormone hepcidin, predominantly produced by hepatocytes, and the iron exporter ferroportin, present in duodenal enterocytes and macrophages. Hepcidin binds to ferroportin to trigger its internalization and lysosomal degradation. 2 In this way, circulating hepcidin controls both intestinal iron absorption and the release of iron from macrophages into the plasma. There are 3 general classes of genetic defects known to cause HH. First, recessive mutations in the gene encoding hepcidin (HAMP) prevent the production of functional peptide. 3 Second, some dominant mutations in ferroportin (encoded by SLC40A1) render it resistant to hepcidin regulation. 4,5 Third, recessive mutations in the genes encoding HFE, transferrin receptor-2 (TFR2) or hemojuvelin (HFE2 or HJV), alter hepcidin expression by the hepatocyte. [6][7][8] Most hemochromatosis patients are homozygous for a C282Y mutation in HFE (equivalent to C294Y in mouse Hfe), an atypical major histocompatibility complex (MHC) class I-like molecule 9 that heterodimerizes with ␤2-microglobulin 10 and associates with the major transferrin receptor (TFR1). 11,12 HFE is similar to MHC class I proteins in that it contains a signal sequence, 3 sequential immunoglobulin superfamily ␣-domains, and a transmembrane domain followed by a 19 amino acid, cytoplasmic domain. The cytoplasmic domain of human HFE has 2 conserved, potential phosphorylation sites at 335 Ser and 342 Tyr. Although it has been shown that the cytoplasmic domains of Class I MHC proteins are not necessary for transmitting T-cell activation signals, 13 and overexpression of HFE proteins containing either a S335M or Y342C mutation decreased ferritin levels in HEK293 cells, 14 we hypothesized that these 2 phosphorylation sites might be involved in HFE-mediated hepcidin induction in vivo. Cytoplasmic motifs similar to the YVLA ( 342 Tyr) motif in HFE function ...

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Section: Discussionmentioning

confidence: 92%

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Schmidt

Andrews

Fleming

2010

Blood

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“…25, 39, and 42-44). It was originally proposed that CHOP inhibited transcription by simple DNA-independent titration of these family members, and this appears to be the case in at least some instances (25,31). However, CHOP can also bind to DNA when in complex with other proteins, including both C/EBP family members and ATF family members (45,46).…”

Section: Discussionmentioning

confidence: 99%

C/EBP Homologous Protein (CHOP) Contributes to Suppression of Metabolic Genes during Endoplasmic Reticulum Stress in the Liver

Chikka

McCabe

Tyra

et al. 2013

Journal of Biological Chemistry

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Background: ER stress regulates metabolic gene expression in liver. Results: The ER stress-regulated pro-apoptotic transcription factor CHOP binds to the promoters of metabolic genes and is necessary for their suppression. Conclusion: CHOP contributes to the metabolic alterations that accompany ER stress in vivo. Significance: These findings suggest that CHOP has a non-apoptotic role in regulating metabolic physiology.

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“…ER stress was directly linked to the acute inflammatory response when it was demonstrated that the ER stress-activated transcription factor CREBH (cyclic AMP-response element-binding protein H) responds to induction by both LPS and IL-6 (91). Importantly, hepcidin expression can be modulated by the transcription factors CHOP (CCAAT-enhancer-binding protein homologous protein), C/EBP␣ (CCAAT-enhancer-binding protein ␣), and CREBH, which bind to specific binding sites on the hepcidin promoter (92,93).…”

Section: Other Causes Of the Anemia Of Inflammationmentioning

confidence: 99%

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

Schmidt

2015

Journal of Biological Chemistry

128

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Iron is a redox-active metal required as a cofactor in multiple metalloproteins essential for a host of life processes. The metal is highly toxic when present in excess and must be strictly regulated to prevent tissue and organ damage. Hepcidin, a molecule first characterized as an antimicrobial peptide, plays a critical role in the regulation of iron homeostasis. Multiple stimuli positively influence the expression of hepcidin, including iron, inflammation, and infection by pathogens. In this Minireview, I will discuss how inflammation regulates hepcidin transcription, allowing for sufficient concentrations of iron for organismal needs while sequestering the metal from infectious pathogens.Iron is crucial for many life functions in both eukaryotic hosts and prokaryotic pathogens. Due to its ability to readily accept or donate electrons, iron is a valuable cofactor in proteins essential in metabolic processes. However, when left unsupervised, iron can also react with oxygen to generate radical oxygen species that can damage all facets of a cell, leading to tissue damage and eventual organ failure. Therefore, it is crucial for organisms to maintain strict control over iron uptake and distribution to assure appropriate amounts for life requirements, yet regulate and sequester it tightly to prevent oxidative stress or microbial proliferation during infection. Herein, I will present an overview of how iron balance is maintained in vertebrate organisms and discuss the role of hepcidin, the master regulator of iron metabolism, in iron regulation during inflammation and infection. General Iron HomeostasisEach day the average human must absorb 1-2 mg of iron from the diet to offset unregulated losses from general bleeding, menstruation, or the sloughing of epithelial cells. Iron is a critical cofactor required for DNA synthesis, mitochondrial respiration, and various signaling pathways. Most crucially, almost 25 mg of iron per day is required for hemoglobin synthesis and the replacement of an estimated 200 billion RBCs. The vast majority of this iron pool is acquired through the recycling of senescent erythrocytes by macrophages of the reticuloendothelial compartment. Whole body iron homeostasis is thought to occur completely at the level of iron absorption, as no physiologically regulated means of iron excretion has been elucidated. Hence, influx of iron from the diet, and recycling of iron from aged or damaged RBCs, must be closely regulated to prevent iron-restricted erythropoiesis resulting in anemia or excess iron loading and subsequent tissue damage caused by the generation of radical oxygen species. Proper distribution of circulating iron to tissues such as the brain, heart, and skeletal muscle is crucial for the prevention of human disease states.Non-heme dietary reduced iron is admitted into the body through divalent metal transporter 1 (DMT1, Slc11a2) (1, 2), an iron transporter located on the apical membrane of duodenal enterocytes located in the first section of the small intestine ( Fig. 1). After uptake in...

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ER Stress-Inducible Factor CHOP Affects the Expression of Hepcidin by Modulating C/EBPalpha Activity

Cited by 90 publications

References 41 publications

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

C/EBP Homologous Protein (CHOP) Contributes to Suppression of Metabolic Genes during Endoplasmic Reticulum Stress in the Liver

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

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