Hepatocyte growth factor activator inhibitor type 2 (HAI-2) modulates hepcidin expression by inhibiting cell surface protease matriptase-2

Matriptase-2, a recently identified cell surface protease is the key enzyme of iron homeostasis modulating the expression of the liver peptide hormone hepcidin. Hepatocyte growth factor activator inhibitors type 1 and 2 (HAI-1 and HAI-2) 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 media. 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 media 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 hemojuvelin (HJV). Altogether, our study 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 homeostasis, with clinical importance for a treatment of iron overload diseases.

Source: BJ Cell - January 8, 2013 Category: Biochemistry Authors: E Maurer, M Gütschow, M Stirnberg Tags: BJ Cell Source Type: research