Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism.
Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism.
复制标题
DOI：
10.1016/j.jbc.2023.105238
复制
发表时间：
2023-10
影响因子：
4.8
通讯作者：
Zhang, An-Sheng
中科院分区：
文献类型：
--
作者：
Enns, Caroline A.;Weiskopf, Tyler;Zhang, Richard H.;Wu, Jeffrey;Jue, Shall;Kawaguchi, Makiko;Kataoka, Hiroaki;Zhang, An-Sheng
MATRIPTASE-2(MT2)是由TMPRSS6编码的一种膜固定型丝氨酸蛋白酶。它通过抑制铁调节激素海普西丁，在铁的动态平衡中发挥关键作用。缺乏功能性MT2会导致不适当的高海普西丁和铁耐受性缺铁性贫血。MT2在体外切割海普西丁诱导途径的多个组分。它被膜锚定的丝氨酸蛋白酶抑制剂HAI-2抑制。早些时候的体内研究表明，MT2可以抑制海普西丁的表达，而不是依赖于它的蛋白分解活性。在这项研究中，我们的数据表明，肝脏MT2是抑制海普西丁的限制因素。在Tmprss 6−/−小鼠身上的研究表明，将膳食铁增加到∼0.5%足以克服高海普西丁屏障，纠正缺铁性贫血。有趣的是，Tmprss 6−/−小鼠体内铁的增加能够进一步上调海普西丁的表达，其幅度与野生型小鼠相似。这些结果表明，MT2的缺乏并不影响海普西丁的铁诱导。对野生型MT2和蛋白水解型死亡形式fMt2S762a的进一步研究表明，MT2的功能是以一种主要依赖于其非蛋白分解作用的方式降低海普西丁的基础表达水平。HAI-2对小鼠肝细胞特异性消融的研究支持了这一观点，该研究显示HAI-2对铁稳态的影响微乎其微，而海普西丁对铁的调节没有显著影响。综上所述，这些观察表明，MT2的功能是设定海普西丁表达的基础水平，这一过程主要是通过非蛋白分解机制完成的。
Matriptase-2 (MT2), encoded by TMPRSS6, is a membrane-anchored serine protease. It plays a key role in iron homeostasis by suppressing the iron-regulatory hormone, hepcidin. Lack of functional MT2 results in an inappropriately high hepcidin and iron-refractory iron-deficiency anemia. Mt2 cleaves multiple components of the hepcidin-induction pathway in vitro. It is inhibited by the membrane-anchored serine protease inhibitor, Hai-2. Earlier in vivo studies show that Mt2 can suppress hepcidin expression independently of its proteolytic activity. In this study, our data indicate that hepatic Mt2 was a limiting factor in suppressing hepcidin. Studies in Tmprss6−/− mice revealed that increases in dietary iron to ∼0.5% were sufficient to overcome the high hepcidin barrier and to correct iron-deficiency anemia. Interestingly, the increased iron in Tmprss6−/− mice was able to further upregulate hepcidin expression to a similar magnitude as in wild-type mice. These results suggest that a lack of Mt2 does not impact the iron induction of hepcidin. Additional studies of wild-type Mt2 and the proteolytic-dead form, fMt2S762A, indicated that the function of Mt2 is to lower the basal levels of hepcidin expression in a manner that primarily relies on its nonproteolytic role. This idea is supported by the studies in mice with the hepatocyte-specific ablation of Hai-2, which showed a marginal impact on iron homeostasis and no significant effects on iron regulation of hepcidin. Together, these observations suggest that the function of Mt2 is to set the basal levels of hepcidin expression and that this process is primarily accomplished through a nonproteolytic mechanism.
登录
查看更多内容
影响因子：
20.3
作者：
Finberg, Karin E.;Whittlesey, Rebecca L.;Andrews, Nancy C.
通讯作者：
Andrews, Nancy C.
影响因子：
20.3
作者：
Charlebois, Edouard;Fillebeen, Carine;Pantopoulos, Kostas
通讯作者：
Pantopoulos, Kostas
影响因子：
20.3
作者：
Canali, Susanna;Zumbrennen-Bullough, Kimberly B.;Babitt, Jodie L.
通讯作者：
Babitt, Jodie L.
影响因子：
20.3
作者：
Aschemeyer, Sharraya;Qiao, Bo;Nemeth, Elizabeta
通讯作者：
Nemeth, Elizabeta
影响因子：
3.7
作者：
Frýdlová J;Přikryl P;Truksa J;Falke LL;Du X;Gurieva I;Vokurka M;Krijt J
通讯作者：
Krijt J