The immunophilin FKBP12 inhibits hepcidin expression by binding the BMP type I receptor ALK2 in hepatocytes
Visual Abstract <img class="highwire-fragment fragment-image" alt="Figure1" src="http://www.bloodjournal.org/content/bloodjournal/130/19/2111/F1.medium.gif" width="440" height="357"/>Download figureOpen in new tabDownload powerpoint The express...
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
September 1, 2017
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| In: |
Blood
Year: 2017, Jahrgang: 130, Heft: 19, Pages: 2111-2120 |
| ISSN: | 1528-0020 |
| DOI: | 10.1182/blood-2017-04-780692 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1182/blood-2017-04-780692 Verlag, kostenfrei, Volltext: http://www.bloodjournal.org/content/130/19/2111 
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| Verfasserangaben: | Silvia Colucci, Alessia Pagani, Mariateresa Pettinato, Irene Artuso, Antonella Nai, Clara Camaschella and Laura Silvestri |
| Zusammenfassung: | Visual Abstract <img class="highwire-fragment fragment-image" alt="Figure1" src="http://www.bloodjournal.org/content/bloodjournal/130/19/2111/F1.medium.gif" width="440" height="357"/>Download figureOpen in new tabDownload powerpoint 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. |
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| Beschreibung: | Gesehen am 17.08.2018 |
| Beschreibung: | Online Resource |
| ISSN: | 1528-0020 |
| DOI: | 10.1182/blood-2017-04-780692 |