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

Silvia Colucci, Alessia Pagani, M Pettinato, I Artuso, A Nai, C Camaschella, L Silvestri

Research output: Contribution to journalArticle

8 Citations (Scopus)

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. © 2017 by The American Society of Hematology.
Original languageEnglish
Pages (from-to)2111-2120
Number of pages10
JournalBlood
Volume130
Issue number19
DOIs
Publication statusPublished - 2017

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Type I Bone Morphogenetic Protein Receptors
Tacrolimus Binding Protein 1A
Immunophilins
Hepcidins
Hepatocytes
Tacrolimus
Sirolimus
Iron
Bone Morphogenetic Protein Receptors
Ligands
Homeostasis
Inflammation

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The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes. / Colucci, Silvia; Pagani, Alessia; Pettinato, M; Artuso, I; Nai, A; Camaschella, C; Silvestri, L.

In: Blood, Vol. 130, No. 19, 2017, p. 2111-2120.

Research output: Contribution to journalArticle

Colucci, Silvia ; Pagani, Alessia ; Pettinato, M ; Artuso, I ; Nai, A ; Camaschella, C ; Silvestri, L. / The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes. In: Blood. 2017 ; Vol. 130, No. 19. pp. 2111-2120.
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