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dc.contributor.authorWahedi, Mastura
dc.contributor.authorWortham, Aaron M.
dc.contributor.authorKleven, Mark D.
dc.contributor.authorZhao, Ningning
dc.contributor.authorJue, Shall
dc.contributor.authorEnns, Caroline A.
dc.contributor.authorZhang, An-Sheng
dc.date.accessioned2017-12-04T23:50:13Z
dc.date.available2017-12-04T23:50:13Z
dc.date.issued2017-11-03
dc.identifier.citationMatriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathway 2017, 292 (44):18354 Journal of Biological Chemistryen
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.pmid28924039
dc.identifier.doi10.1074/jbc.M117.801795
dc.identifier.urihttp://hdl.handle.net/10150/626185
dc.description.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.
dc.description.sponsorshipNational Institutes of Health [R01DK102791, R01DK072166, R00DK104066]en
dc.language.isoenen
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INCen
dc.relation.urlhttp://www.jbc.org/lookup/doi/10.1074/jbc.M117.801795en
dc.rights© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.en
dc.subjectbone morphogenetic protein (BMP)en
dc.subjectironen
dc.subjectliveren
dc.subjectreceptoren
dc.subjectsignalingen
dc.subjectHFEen
dc.subjecthemojuvelinen
dc.subjecthepcidinen
dc.subjectmatriptase-2en
dc.subjecttransferrin receptor-2en
dc.titleMatriptase-2 suppresses hepcidin expression by cleaving multiple components of the hepcidin induction pathwayen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Dept Nutr Scien
dc.identifier.journalJournal of Biological Chemistryen
dc.description.note12 month embargo; Published online: 18 September 2017en
dc.description.collectioninformationThis 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.en
dc.eprint.versionFinal published versionen
html.description.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.


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