TMPRSS6-mediated regulation of iron via cleavage of components of the bone morphogenetic protein signaling pathway in liver and bone

铁的调节对肝脏和骨骼的动态平衡至关重要。跨膜丝氨酸蛋白酶6(TMPRSS6)与骨形态发生蛋白(BMP)信号通路的多个组成部分相互作用，包括BMP I型受体ALK2和ALK3，从而减少铁调节激素海普西丁的表达。从生理上讲，如果血清铁水平达到足够的水平，海普西丁就会与铁出口商铁蛋白结合并使其失活。TMPRSS6功能突变的丧失会导致抗铁缺铁性贫血，这是由于海普西丁水平过高所致。尽管TMPRSS6的结合和在系统铁稳态和肝脏调节中的功能已经被研究，但对这个调节系统的详细了解仍然是难以捉摸的。本项目的总体目标是深入研究TMPRSS6的信号机制和结合。因此，我们将集中于三个主要目标：1)在TMPRSS6与BMP受体和铁调节蛋白HFE、Hjv、Tfr1和Tfr2相互作用的电子模拟中，2)在小鼠模型中研究TMPRSS6与BMP信号通路组件和其他铁调节蛋白的相互作用，以及3)评估TMPRSS6在骨细胞中的重要性。此外，我们还将研究系统铁稳态的变化是否会损害信号机制，哪些因素会发生，以及激活或阻断如何影响结合和受体的形成。这项提议将揭开TMPRSS6在肝脏、铁感应和骨骼中的作用机制。

The regulation of iron is crucial for liver and bone homeostasis. The transmembrane serine protease 6 (TMPRSS6) interacts with multiple components of the bone morphogenetic protein (BMP) signaling pathway including the BMP type I receptors ALK2 and ALK3, and thereby reduces the expression of the iron regulatory hormone hepcidin. Physiologically, hepcidin binds to and inactivates the iron exporter ferroportin if serum iron levels have reached sufficient levels. The loss of function mutation in TMPRSS6 causes iron-resistant-iron deficient anemia due to inappropriately high hepcidin levels. Even though aspects of TMPRSS6 binding and function in systemic iron homeostasis and liver regulation have been investigated, a detailed understanding of this regulatory system is elusive. The overall aim of this project is to investigate in depth signaling mechanisms and binding of TMPRSS6. Therefore, we will focus on the three main goals: 1) in silico-modeling of TMPRSS6 interactions with BMP receptors and the iron regulatory proteins Hfe, Hjv, Tfr1 and Tfr2, 2) investigation of TMPRSS6 interactions with components of the BMP signaling pathway and other iron regulatory proteins in vivo in mouse models, and 3) assessing the importance of TMPRSS6 in bone cells. In addition, we will investigate whether changes of systemic iron homeostasis impair the signaling mechanisms, which contributing factors occur, and how activation or blockage affects binding and receptor formation. This proposal will unravel mechanisms of TMPRSS6 actions in liver, iron sensing, and bone.