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The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes

Silvia Colucci, Alessia Pagani, Mariateresa Pettinato, Irene Artuso, Antonella Nai, Clara Camaschella and Laura Silvestri

Key Points

  • FKBP12 suppresses hepcidin by interaction with the BMP receptor ALK2.

  • Disruption of FKBP12–ALK2 interaction increases hepcidin and renders the receptor responsive to the inflammatory ligand Activin A.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

Abstract

The expression of the key regulator of iron homeostasis hepcidin is activated by the BMP-SMAD pathway in response to iron and inflammation and among drugs, by rapamycin, which inhibits mTOR in complex with the immunophilin FKBP12. FKBP12 interacts with BMP type I receptors to avoid uncontrolled signaling. By pharmacologic and genetic studies, we identify FKBP12 as a novel hepcidin regulator. Sequestration of FKBP12 by rapamycin or tacrolimus activates hepcidin both in vitro and in murine hepatocytes. Acute tacrolimus treatment transiently increases hepcidin in wild-type mice. FKBP12 preferentially targets the BMP receptor ALK2. ALK2 mutants defective in binding FKBP12 increase hepcidin expression in a ligand-independent manner, through BMP-SMAD signaling. ALK2 free of FKBP12 becomes responsive to the noncanonical inflammatory ligand Activin A. Our results identify a novel hepcidin regulator and a potential therapeutic target to increase defective BMP signaling in disorders of low hepcidin.

  • Submitted April 20, 2017.
  • Accepted August 31, 2017.
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