Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway
Wortham, Aaron M.
Kleven, Mark D.
Enns, Caroline A.
AffiliationUniv Arizona, Dept Nutr Sci
Keywordsbone morphogenetic protein (BMP)
MetadataShow full item record
CitationMatriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway 2017, 292 (44):18354 Journal of Biological Chemistry
JournalJournal of Biological Chemistry
Rights© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractSystemic 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.
Note12 month embargo; Published online: 18 September 2017
VersionFinal published version
SponsorsNational Institutes of Health [R01DK102791, R01DK072166, R00DK104066]
CollectionsUA Faculty Publications
- Neogenin Facilitates the Induction of Hepcidin Expression by Hemojuvelin in the Liver.
- Authors: Zhao N, Maxson JE, Zhang RH, Wahedi M, Enns CA, Zhang AS
- Issue date: 2016 Jun 3
- Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice.
- Authors: Ramos E, Kautz L, Rodriguez R, Hansen M, Gabayan V, Ginzburg Y, Roth MP, Nemeth E, Ganz T
- Issue date: 2011 Apr
- Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin.
- Authors: Latour C, Besson-Fournier C, Meynard D, Silvestri L, Gourbeyre O, Aguilar-Martinez P, Schmidt PJ, Fleming MD, Roth MP, Coppin H
- Issue date: 2016 Jan
- Low intracellular iron increases the stability of matriptase-2.
- Authors: Zhao N, Nizzi CP, Anderson SA, Wang J, Ueno A, Tsukamoto H, Eisenstein RS, Enns CA, Zhang AS
- Issue date: 2015 Feb 13
- Neogenin interacts with matriptase-2 to facilitate hemojuvelin cleavage.
- Authors: Enns CA, Ahmed R, Zhang AS
- Issue date: 2012 Oct 12