Colucci Silvia, Pagani Alessia, Pettinato Mariateresa, Artuso Irene, Nai Antonella, Camaschella Clara, Silvestri Laura
Vita Salute University and Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
Blood. 2017 Nov 9;130(19):2111-2120. doi: 10.1182/blood-2017-04-780692. Epub 2017 Sep 1.
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.
铁稳态关键调节因子铁调素的表达，在铁和炎症刺激下，通过骨形态发生蛋白（BMP）-SMAD信号通路被激活；在药物中，雷帕霉素也可激活该通路，雷帕霉素可抑制与亲免素FKBP12形成复合物的哺乳动物雷帕霉素靶蛋白（mTOR）。FKBP12与BMP I型受体相互作用，以避免信号失控。通过药理学和遗传学研究，我们确定FKBP12是一种新型的铁调素调节因子。雷帕霉素或他克莫司对FKBP12的螯合作用，在体外和小鼠肝细胞中均可激活铁调素。急性他克莫司治疗可使野生型小鼠的铁调素短暂增加。FKBP12优先靶向BMP受体ALK2。与FKBP12结合存在缺陷的ALK2突变体，通过BMP-SMAD信号传导，以不依赖配体的方式增加铁调素表达。不含FKBP12的ALK2对非经典炎性配体激活素A有反应。我们的研究结果确定了一种新型的铁调素调节因子，以及一个潜在的治疗靶点，可用于增加低铁调素疾病中缺陷的BMP信号传导。
