title: Hepatocyte growth factor activator inhibitor type 2 (HAI-2) modulates hepcidin expression by inhibiting the cell surface protease matriptase-2.
abstract: Matriptase-2, a recently identified cell surface protease, is the key enzyme of iron homoeostasis modulating the expression of the liver peptide hormone hepcidin. HAI (hepatocyte growth factor activator inhibitor) types 1 and 2 (HAI-1 and HAI-2 respectively) have been shown to inhibit the close homologue, i.e. matriptase. By co-expressing matriptase-2 and the inhibitor HAI-2 we have identified HAI-2 displaying high inhibitory potential against matriptase-2 at the cell surface as well as in conditioned medium. Accordingly, complex formation between matriptase-2 and HAI-2 was demonstrated by isolation of the complex via immobilizing either HAI-2 or matriptase-2 from lysates and conditioned medium of co-expressing cells. Furthermore, HAI-2 indirectly influences the expression of the hepcidin-encoding gene HAMP. The inhibitor abrogates the matriptase-2-mediated suppression of HAMP expression, presumably by inhibiting the supposed potential of matriptase-2 to cleave membrane-bound HJV (haemojuvelin). Taken together, the results of the present study have characterized HAI-2 as an inhibitor of matriptase-2 that modulates the synthesis of hepcidin and provides new insights into the regulatory mechanism of iron homoeostasis, with clinical importance for a treatment of iron overload diseases.
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Maurer
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.forename: Marit
authors.initials: M
authors.lastname: Stirnberg
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism; D032701:Biomimetics; D015687:Cell Hypoxia / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000494:pharmacology; D000090463:Iron Deficiencies; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism; D057057:Serine Proteases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C109148:SPINT2 protein, human; D015842:Serine Proteinase Inhibitors; D007501:Iron; D057057:Serine Proteases; D012697:Serine Endopeptidases; C467801:matriptase 2