Chen Simeng, Feng Teng, Vujić Spasić Maja, Altamura Sandro, Breitkopf-Heinlein Katja, Altenöder Jutta, Weiss Thomas S, Dooley Steven, Muckenthaler Martina U
From the Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg, 69117 Heidelberg, Germany, the Department of Medicine II, Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany, the Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany, and.
the Department of Medicine II, Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
J Biol Chem. 2016 Jun 17;291(25):13160-74. doi: 10.1074/jbc.M115.691543. Epub 2016 Apr 27.
The hepatic hormone hepcidin is the master regulator of systemic iron homeostasis. Its expression level is adjusted to alterations in iron levels, inflammatory cues, and iron requirements for erythropoiesis. Bone morphogenetic protein 6 (BMP6) contributes to the iron-dependent control of hepcidin. In addition, TGF-β1 may stimulate hepcidin mRNA expression in murine hepatocytes and human leukocytes. However, receptors and downstream signaling proteins involved in TGF-β1-induced hepcidin expression are still unclear. Here we show that TGF-β1 treatment of mouse and human hepatocytes, as well as ectopic expression of TGF-β1 in mice, increases hepcidin mRNA levels. The hepcidin response to TGF-β1 depends on functional TGF-β1 type I receptor (ALK5) and TGF-β1 type II receptor (TβRII) and is mediated by a noncanonical mechanism that involves Smad1/5/8 phosphorylation. Interestingly, increasing availability of canonical Smad2/3 decreases TGF-β1-induced hepcidin regulation, whereas the BMP6-hepcidin signal was enhanced, indicating a signaling component stoichiometry-dependent cross-talk between the two pathways. Although ALK2/3-dependent hepcidin activation by BMP6 can be modulated by each of the three hemochromatosis-associated proteins: HJV (hemojuvelin), HFE (hemochromatosis protein), and TfR2 (transferrin receptor 2), these proteins do not control the ALK5-mediated hepcidin response to TGF-β1. TGF-β1 mRNA levels are increased in mouse models of iron overload, indicating that TGF-β1 may contribute to hepcidin synthesis under these conditions. In conclusion, these data demonstrate that a complex regulatory network involving TGF-β1 and BMP6 may control the sensing of systemic and/or hepatic iron levels.
肝脏激素铁调素是全身铁稳态的主要调节因子。其表达水平会根据铁水平、炎症信号以及红细胞生成所需铁量的变化进行调整。骨形态发生蛋白6（BMP6）参与铁对铁调素的依赖性调控。此外，转化生长因子-β1（TGF-β1）可能刺激小鼠肝细胞和人白细胞中铁调素mRNA的表达。然而，参与TGF-β1诱导铁调素表达的受体和下游信号蛋白仍不清楚。在此，我们表明，用TGF-β1处理小鼠和人肝细胞，以及在小鼠体内异位表达TGF-β1，均可增加铁调素mRNA水平。铁调素对TGF-β1的反应依赖于功能性TGF-β1Ⅰ型受体（ALK5）和TGF-β1Ⅱ型受体（TβRII），并由一种涉及Smad1/5/8磷酸化的非经典机制介导。有趣的是，增加经典Smad2/3的可用性会降低TGF-β1诱导的铁调素调控，而BMP6-铁调素信号则增强，这表明两条通路之间存在信号成分化学计量依赖性的相互作用。尽管BMP6通过ALK2/3依赖性激活铁调素可受到三种与血色素沉着症相关的蛋白（血色素沉着症相关蛋白HJV、血色素沉着症蛋白HFE和转铁蛋白受体2 TfR2）中任何一种的调节，但这些蛋白并不控制ALK5介导的铁调素对TGF-β1的反应。在铁过载的小鼠模型中，TGF-β1 mRNA水平升高，表明在这些条件下TGF-β1可能参与铁调素的合成。总之，这些数据表明，一个涉及TGF-β1和BMP6的复杂调控网络可能控制全身和/或肝脏铁水平的感知。
