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

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    Name:
    J.Biol.Chem.-2017-Wahedi-18354 ...
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    3.392Mb
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    Description:
    Final Published Version
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    Author
    Wahedi, Mastura
    Wortham, Aaron M.
    Kleven, Mark D.
    Zhao, Ningning
    Jue, Shall
    Enns, Caroline A.
    Zhang, An-Sheng
    Affiliation
    Univ Arizona, Dept Nutr Sci
    Issue Date
    2017-11-03
    Keywords
    bone morphogenetic protein (BMP)
    iron
    liver
    receptor
    signaling
    HFE
    hemojuvelin
    hepcidin
    matriptase-2
    transferrin receptor-2
    
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    Publisher
    AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
    Citation
    Matriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway 2017, 292 (44):18354 Journal of Biological Chemistry
    Journal
    Journal of Biological Chemistry
    Rights
    © 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 2017
    ISSN
    0021-9258
    1083-351X
    PubMed ID
    28924039
    DOI
    10.1074/jbc.M117.801795
    Version
    Final published version
    Sponsors
    National Institutes of Health [R01DK102791, R01DK072166, R00DK104066]
    Additional Links
    http://www.jbc.org/lookup/doi/10.1074/jbc.M117.801795
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.M117.801795
    Scopus Count
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