title: Low intracellular iron increases the stability of matriptase-2.
abstract: Matriptase-2 (MT2) is a type II transmembrane serine protease that is predominantly expressed in hepatocytes. It suppresses the expression of hepatic hepcidin, an iron regulatory hormone, by cleaving membrane hemojuvelin into an inactive form. Hemojuvelin is a bone morphogenetic protein (BMP) co-receptor. Here, we report that MT2 is up-regulated under iron deprivation. In HepG2 cells stably expressing the coding sequence of the MT2 gene, TMPRSS6, incubation with apo-transferrin or the membrane-impermeable iron chelator, deferoxamine mesylate salt, was able to increase MT2 levels. This increase did not result from the inhibition of MT2 shedding from the cells. Rather, studies using a membrane-permeable iron chelator, salicylaldehyde isonicotinoyl hydrazone, revealed that depletion of cellular iron was able to decrease the degradation of MT2 independently of internalization. We found that lack of the putative endocytosis motif in its cytoplasmic domain largely abolished the sensitivity of MT2 to iron depletion. Neither acute nor chronic iron deficiency was able to alter the association of Tmprss6 mRNA with polyribosomes in the liver of rats indicating a lack of translational regulation by low iron levels. Studies in mice showed that Tmprss6 mRNA was not regulated by iron nor the BMP-mediated signaling with no evident correlation with either Bmp6 mRNA or Id1 mRNA, a target of BMP signaling. These results suggest that regulation of MT2 occurs at the level of protein degradation rather than by changes in the rate of internalization and translational or transcriptional mechanisms and that the cytoplasmic domain of MT2 is necessary for its regulation.
authors.affiliation: From the Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239.
authors.forename: Ningning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: the Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nizzi
authors.affiliation: the Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Anderson
authors.affiliation: the Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, and.
authors.forename: Jiaohong
authors.initials: J
authors.lastname: Wang
authors.affiliation: the Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, and.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ueno
authors.affiliation: the Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, and the Department of Veteran Affairs, Greater Los Angeles Healthcare System, Los Angeles, California 90073.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: the Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Eisenstein
authors.affiliation: From the Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Enns
authors.affiliation: From the Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239, zhanga@ohsu.edu.
authors.forename: An-Sheng
authors.initials: AS
authors.lastname: Zhang
mesh_terms: D000818:Animals; D019921:Biotinylation; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D000071020:Hemochromatosis Protein; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D000090463:Iron Deficiencies; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D019485:Bone Morphogenetic Proteins; D058851:GPI-Linked Proteins; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D012697:Serine Endopeptidases; C467801:matriptase 2
keywords: BMP Signaling; Iron; Liver; Matriptase-2; Protein Degradation; Transcription; Translation