1. Schematic representation of a model of matriptase-2 activity in iron deficiency. On the left, the serine protease cleaves m-HJV releasing soluble fragments (here simplified by the black boxes). The cleavage sites of matriptase-2 are unknown. The question mark indicates uncertainty on fragments’ function. The resulting hepcidin inhibition is shown. The complementary effect of s-HJV, produced by furin cleavage, to sequester BMP is shown on the right. 2. Lack of hepcidin inhibition in the presence of matriptase-2 mutations. m-HJV acts as BMP co-receptor and permits hepcidin production in iron deficiency; the effect of s-HJV cannot down-regulate hepcidin in the presence of m-HJV. Reprinted from Silvestri L, Pagani A, Nai A, et al. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metabolism. 2008;8:502-11. With permission from Elsevier.