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.

铁稳态铁调皮素的关键调节因子的表达被BMP-SMAD途径激活，以响应铁和炎症，并且在药物中被雷帕霉素激活，雷帕霉素可抑制与亲免蛋白FKBP12结合的mTOR。FKBP12与BMP I型受体相互作用，以避免不受控制的信号传导。通过药理和遗传研究，我们确定FKBP12为新型hepcidin调节剂。雷帕霉素或他克莫司对FKBP12的隔离在体外和在鼠肝细胞中均激活了hepcidin。急性他克莫司治疗可在野生型小鼠中短暂增加铁调素。FKBP12优先靶向BMP受体ALK2。有缺陷的结合FKBP12的ALK2突变体通过BMP-SMAD信号传导以配体独立的方式增加铁调素的表达。不含FKBP12的ALK2对非规范性炎症配体激活素A产生反应。