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

Abstract

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.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

Improvement in Parameters of Hematologic and Immunologic Function and Patient Well-being in the Phase III RESONATE Study of Ibrutinib Versus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

“…Cost implications were not analyzed, although one recent real-world analysis of front line CLL treatment showed reduced medical resource utilization and reduced costs of care are incurred with ibrutinib compared with chemoimmunotherapy. 28 That analysis did not evaluate pharmacy costs, and it remains unknown how these will contribute to the balance of costs for ibrutinib versus chemoimmunotherapy options. Such evaluations will be of further interest in the real-world setting.…”

Hemochromatosis proteins are dispensable for the acute hepcidin response to BMP2

“… 2 , 3 BMP type II receptors show a redundant function in hepcidin regulation in vivo , while ALK2 and ALK3 have a non-redundant role. The current model suggests that ALK2 is mainly involved in BMP6-dependent hepcidin upregulation in conditions of iron overload 4 and is inhibited by FKBP12, 5 whereas ALK3 maintains basal hepcidin expression 4 and signals preferentially in response to BMP2. 6 , 7 Hereditary hemochromatosis (HH), characterized by iron overload due to inappropriately low hepcidin production, is caused by mutations in HFE , the second transferrin receptor ( TFR2 ), hemojuvelin ( HJV ) and hepcidin ( HAMP ).…”

“… BMP2 up-regulates hepcidin and Id1 expression in murine primary hepatocytes lacking Hjv, Tfr2 or Hfe . (A) Primary murine hepatocytes from 3 or 4 wild-type (WT) male mice maintained on a Sv129 or C57BL/6J background, respectively, were isolated as described 5 and treated for 4 hours (h) with increasing concentrations of BMP2 (1-100 ng/mL as indicated). Total RNA was isolated and retrotranscribed, and quantitative real-time polymerase chain reaction (qRTPCR) was performed to analyze hepcidin (Hamp) expression.…”

Iron Metabolism in Cancer

“…Tumor-associated fibroblasts induce hepcidin expression via paracrine IL-6-BMP signaling, and this induction facilitates breast cancer cells growth [161]. Whereas the immunophilin FKBP12 represses hepcidin expression by binding the BMP type I receptor ALK2 and blocking BMP-SMAD pathway in hepatoma cells [162]. These findings may pave the way for using hepcidin targeting as a novel treatment for iron homeostasis in tumor tissue and the tumor microenvironment.…”