Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway
Name:
J.Biol.Chem.-2017-Wahedi-18354 ...
Size:
3.392Mb
Format:
PDF
Description:
Final Published Version
Author
Wahedi, MasturaWortham, Aaron M.
Kleven, Mark D.
Zhao, Ningning
Jue, Shall
Enns, Caroline A.
Zhang, An-Sheng
Affiliation
Univ Arizona, Dept Nutr SciIssue Date
2017-11-03Keywords
bone morphogenetic protein (BMP)iron
liver
receptor
signaling
HFE
hemojuvelin
hepcidin
matriptase-2
transferrin receptor-2
Metadata
Show full item recordCitation
Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway 2017, 292 (44):18354 Journal of Biological ChemistryJournal
Journal of Biological ChemistryRights
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.Collection Information
This 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 repository@u.library.arizona.edu.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.Note
12 month embargo; Published online: 18 September 2017ISSN
0021-92581083-351X
PubMed ID
28924039Version
Final published versionSponsors
National Institutes of Health [R01DK102791, R01DK072166, R00DK104066]Additional Links
http://www.jbc.org/lookup/doi/10.1074/jbc.M117.801795ae974a485f413a2113503eed53cd6c53
10.1074/jbc.M117.801795
Scopus Count
Collections
Related articles
- 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
- The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin.
- Authors: Mao P, Wortham AM, Enns CA, Zhang AS
- Issue date: 2019 Feb 8
- Neogenin interacts with matriptase-2 to facilitate hemojuvelin cleavage.
- Authors: Enns CA, Ahmed R, Zhang AS
- Issue date: 2012 Oct 12
- 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
- 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