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Science 325 (5942): 877-880

Copyright © 2009 by the American Association for the Advancement of Science

ER Stress Controls Iron Metabolism Through Induction of Hepcidin

Chiara Vecchi,1 Giuliana Montosi,1 Kezhong Zhang,2 Igor Lamberti,1 Stephen A. Duncan,3 Randal J. Kaufman,4 Antonello Pietrangelo1,*

Abstract: 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.

1 Center for Hemochromatosis, Department of Internal Medicine, University Hospital Policlinico di Modena, Modena, Italy.
2 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
3 Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
4 Howard Hughes Medical Institute, Departments of Biological Chemistry and Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109–0650, USA.

* To whom correspondence should be addressed. E-mail: antonello.pietrangelo{at}unimore.it

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