Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway

Mastura Wahedi, Aaron M. Wortham, Mark D. Kleven, Ningning Zhao, Shall Jue, Caroline Enns, An-Sheng Zhang

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 thatMT2exerts its inhibitory effect by inactivating HJV. Here, we report that MT2 suppresses hepcidin expression independently of HJV. In Hjv-1-mice, increased expression of exogenousMT2in 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 MT2cleaves 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.

Original languageEnglish (US)
Pages (from-to)18354-18371
Number of pages18
JournalJournal of Biological Chemistry
Volume292
Issue number44
DOIs
StatePublished - 2017

Fingerprint

Hepcidins
Iron
Bone Morphogenetic Protein Receptors
Transferrin Receptors
Liver
Transferrin
matriptase 2
Bone Morphogenetic Proteins
Hep G2 Cells
Recycling
Cell membranes
Duodenum
Homeostasis
Peptide Hydrolases
Erythrocytes
Cell Membrane
Hormones

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway. / Wahedi, Mastura; Wortham, Aaron M.; Kleven, Mark D.; Zhao, Ningning; Jue, Shall; Enns, Caroline; Zhang, An-Sheng.

In: Journal of Biological Chemistry, Vol. 292, No. 44, 2017, p. 18354-18371.

Research output: Contribution to journalArticle

Wahedi, Mastura ; Wortham, Aaron M. ; Kleven, Mark D. ; Zhao, Ningning ; Jue, Shall ; Enns, Caroline ; Zhang, An-Sheng. / Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 44. pp. 18354-18371.
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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 thatMT2exerts its inhibitory effect by inactivating HJV. Here, we report that MT2 suppresses hepcidin expression independently of HJV. In Hjv-1-mice, increased expression of exogenousMT2in 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 MT2cleaves 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.",
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AU - Enns, Caroline

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AB - 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 thatMT2exerts its inhibitory effect by inactivating HJV. Here, we report that MT2 suppresses hepcidin expression independently of HJV. In Hjv-1-mice, increased expression of exogenousMT2in 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 MT2cleaves 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.

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