Abstract
Systemic iron homeostasis is maintained by regulation of iron absorption in the duodenum, iron recycling from erythrocytes, and iron mobilization from the liver and is controlled by the hepatic hormone hepcidin. Hepcidin expression is induced via the bone morphogenetic protein (BMP) signaling pathway that preferentially uses two type I (ALK2 and ALK3) and two type II (ActRIIA and BMPR2) BMP receptors. Hemojuvelin (HJV), HFE, and transferrin receptor-2 (TfR2) facilitate this process presumably by forming a plasma membrane complex with BMP receptors. Matriptase-2 (MT2) is a protease and key suppressor of hepatic hepcidin expression and cleaves HJV. Previous studies have therefore suggested that MT2 exerts its inhibitory effect by inactivating HJV. Here, we report that MT2 suppresses hepcidin expression independently of HJV. In Hjv-/- mice, increased expression of exogenous MT2 in the liver significantly reduced hepcidin expression similarly as observed in wild-type mice. Exogenous MT2 could fully correct abnormally high hepcidin expression and iron deficiency in MT2-/- mice. In contrast to MT2, increased Hjv expression caused no significant changes in wild-type mice, suggesting that Hjv is not a limiting factor for hepcidin expression. Further studies revealed that MT2 cleaves ALK2, ALK3, ActRIIA, Bmpr2, Hfe, and, to a lesser extent, Hjv and Tfr2. MT2-mediated Tfr2 cleavage was also observed in HepG2 cells endogenously expressing MT2 and TfR2. Moreover, iron-loaded transferrin blocked MT2-mediated Tfr2 cleavage, providing further insights into the mechanism of Tfr2's regulation by transferrin. Together, these observations indicate that MT2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway.
Highlights
Systemic iron homeostasis is maintained by regulation of iron absorption in the duodenum, iron recycling from erythrocytes, and iron mobilization from the liver and is controlled by the hepatic hormone hepcidin
The above observations strongly indicate that MT2 cleaves all four Bmp receptors that are involved in hepcidin expression with ALK3 being the most sensitive substrate
We examined whether BMP6 blocks MT2 cleavage of ALK2, ALK3, ActRIIA, Bmpr2, Hfe, Hjv, and Tfr2, because increased bodily iron load elevates hepcidin and BMP6 expression in the liver [8]
Summary
Expression of tagged-MT2 in the liver of MT2؊/؊ mice rescues the anemia and alopecia. MT2Ϫ/Ϫ mice are anemic and have alopecia as a result of low iron levels [31,32,33] Both genders of MT2Ϫ/Ϫ mice displayed alopecia, microcytic anemia, low serum iron, low liver nonheme iron, but high hepatic hepcidin mRNA (Fig. 1, Table 1). These results are consistent with those previously reported for MT2Ϫ/Ϫ mice [31,32,33]. A murine MT2 with a C-terminal FLAG/MYC epitope (Fig. 1A, Table 2) was used to explore the mechanism for MT2 suppression of hepcidin expression. A The abbreviations used are: Hb, hemoglobin; RBC, red blood cells; HCT, hematocrit; MCV, mean cell volume; MCH, mean corpuscular hemoglobin
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