Working model of matriptase-2 regulation of iron homeostasis. a Membrane-anchored matriptase-2 (MTP2) is an active protease cleaving hemojuvelin (HJV) resulting in loss of hemojuvelin, a coreceptor for BMPs, from the hepatocyte cell surface. Nevertheless, BMPs can still upregulate hepcidin expression directly through binding to the BMP receptors in the absence of hemojuvelin. Likewise, inflammatory cytokines such as IL-6 are able to upregulate hepcidin expression in the absence of hemojuvelin. It remains to be determined if matriptase-2-mediated cleavage products of hemojuvelin are able to act as a soluble antagonist for the binding of BMPs to the cognate receptor in the same manner as soluble hemojuvelin (sHJV). b The matriptase-2 mask (MTP2^mask) mutant lacking the protease domain is able to localize to the cell surface and can bind hemojuvelin. Uncleaved hemojuvelin is stable and retained on the cell surface where it is perpetually available to promote BMP-mediated activation of hepcidin expression. The presence of the matriptase-2 mask mutant does not interfere with IL-6-mediated upregulation of hepcidin expression.