ER stress controls iron metabolism through induction of hepcidin.
Hepcidin is a peptide hormone that is secreted by the liver and controls body iron homeostasis. Hepcidin overproduction causes anemia of inflammation, whereas its deficiency leads to hemochromatosis. Inflammation and iron are known extracellular stimuli for hepcidin expression. We found that endoplasmic reticulum (ER) stress also induces hepcidin expression and causes hypoferremia and spleen iron sequestration in mice. CREBH (cyclic AMP response element-binding protein H), an ER stress-activated transcription factor, binds to and transactivates the hepcidin promoter. Hepcidin induction in response to exogenously administered toxins or accumulation of unfolded protein in the ER is defective in CREBH knockout mice, indicating a role for CREBH in ER stress-regulated hepcidin expression. The regulation of hepcidin by ER stress links the intracellular response involved in protein quality control to innate immunity and iron homeostasis.
Vecchi
Chiara
C
Center for Hemochromatosis, Department of Internal Medicine, University Hospital Policlinico di Modena, Modena, Italy.
Montosi
Giuliana
G
Zhang
Kezhong
K
Lamberti
Igor
I
Duncan
Stephen A
SA
Kaufman
Randal J
RJ
Pietrangelo
Antonello
A
D016475:3T3 Cells; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D064451:Hepcidins; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011401:Promoter Regions, Genetic; D017510:Protein Folding; D034622:RNA Interference; D013154:Spleen / Q000378:metabolism; D013312:Stress, Physiological; D015533:Transcriptional Activation
D023181:Antimicrobial Cationic Peptides; C533813:CREB3L3 protein, human; C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D007501:Iron
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