Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis

Abstract

Maintaining the body's levels of iron within precise boundaries is essential for normal physiological function. Alterations of these levels below or above the healthy limit lead to a systemic deficiency or overload in iron. The type-two transmembrane serine protease (TTSP), matriptase-2 (also known as TMPRSS6), is attracting significant amounts of interest due to its recently described role in iron homeostasis. The finding of this regulatory role for matriptase-2 was originally derived from the observation that mice deficient in this protease present with anemia due to elevated levels of hepcidin and impaired intestinal iron absorption. Further in vitro analysis has demonstrated that matriptase-2 functions to suppress bone morphogenetic protein stimulation of hepcidin transcription through cell surface proteolytic processing of the bone morphogenetic protein co-receptor hemojuvelin. Consistently, the anemic phenotype of matriptase-2 knockout mice is mirrored in humans with matripase-2 mutations. Currently, 14 patients with iron-refractory iron deficiency anemia (IRIDA) have been reported to harbor various genetic mutations that abrogate matriptase-2 proteolytic activity. In this review, after overviewing the membrane anchored serine proteases, in particular the TTSP family, we summarize the identification and characterization of matriptase-2 and describe its functional relevance in iron metabolism.

Neogenin Interacts with Matriptase-2 to Facilitate Hemojuvelin Cleavage

“…is predicted to cleave HJV at the cell surface (19,21). We previously showed that neogenin is not required for HJV expression on the plasma membrane by flow cytometry (28).…”

“…This type II transmembrane protease is composed of a short cytoplasmic domain, a transmembrane domain, and a large extracellular domain, which contains a membrane-proximal SEA (sea urchin sperm protein, enteropeptidase, agrin) domain, two CUB (complete protein subcomponents C1r/C1s motif, urchin embryonic growth factor, and BMP1) domains, three low density lipoprotein receptor class A domains, a predicted activation domain, and a C-terminal catalytic domain (Fig. 1A) (19). The MT2 catalytic domain is responsible for the cleavage of HJV at arginine 288, releasing a 36-kDa soluble form of HJV that is incapable of binding BMPs (20) making MT2 a suppressor of hepcidin expression (21).…”

Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6

“…The anemic phenotype of matriptase-2-deficient mice is mirrored in patients with matriptase-2 mutations who present with iron-refractory, iron-deficiency anemia. 11 Indeed, patients with iron-refractory, iron-deficiency anemia show inappropriately high hepcidin levels, 11,14,15 which explain the lack of dietary iron absorption and partial response to parenteral iron treatment. 16 The goal of this study was to characterize the in vivo relationship between matriptase-2 and the iron-regulated ligand of Hjv, Bmp6, by analyzing the role of Bmp6 in the setting of anemia in mice deficient for matriptase-2.…”

“…[6][7][8][9] Recently, the serine protease matriptase-2 (also known as tmprss6) has been connected to this iron pathway [10][11][12] because of its proteolysis of Hjv. 13 Matriptase-2 is a type 2 serine protease that is predominately expressed in the liver (for review 14 ). Matriptase-2-deficient mice 10,12 have very high levels of hepcidin, which lead to the inhibition of dietary iron absorption and cause a severe iron-deficiency anemia phenotype.…”

Iron refractory iron deficiency anemia

“…23 It presents all the expected features of trans-membrane serine proteases, 24 including a large ectodomain with a SEA (Sea urchin sperm protein, Enteropeptidase, Agrin) region, two CUB (Complement factor C1s/C1r, Urchin embryonic growth factor, Bone morphogenic protein) domains, three Low Density Lipoprotein Receptor (LDLR) domains and a C terminal serine protease domain with the conserved Ser, Asp and His residues required for the catalytic activity (Figure 2). …”