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The Ca²⁺-Binding Capacity of Epidermal Furin Is Disrupted by H₂O₂-Mediated Oxidation in Vitiligo

Clinical and Experimental Dermatology/Department of Biomedical Sciences (J.D.S., N.C.J.G., K.U.S.), University of Bradford, and Institute for Pigmentary Disorders in Association with the EM Arndt University Greifswald, Germany and University of Bradford, Bradford, BD7 1DP, United Kingdom; and Department of Dermatology (M.B.), University of Münster, D-41849 Münster, Germany

Address all correspondence and requests for reprints to: Professor Karin U. Schallreuter, Clinical and Experimental Dermatology, University of Bradford, Bradford BD7 1DP, United Kingdom. E-mail: k.schallreuter{at}bradford.ac.uk.

The Ca²⁺-dependent precursor convertase furin is abundantly expressed in epidermal keratinocytes and melanocytes. In this context, it is noteworthy that proopiomelanocortin (POMC) cleavage is also processed by furin, leading to ACTH, β-lipotropin, and β-endorphin. All prohormone convertases including furin are regulated by Ca²⁺. Because numerous epidermal peptides and enzymes are affected by H₂O₂-mediated oxidation, including the POMC-derived peptides -MSH and β-endorphin as shown in the epidermis of patients with vitiligo, we here asked the question of whether furin could also be a possible target for this oxidation mechanism by using immunofluorescence, RT-PCR, Western blotting, Ca²⁺-binding studies, and computer modeling. Our results demonstrate significantly decreased in situ immunoreactivity of furin in the epidermis of patients with progressive vitiligo (n = 10), suggesting H₂O₂-mediated oxidation. This was confirmed by ⁴⁵Ca²⁺-binding studies with human recombinant furin identifying the loss of one Ca²⁺-binding site from the enzyme after oxidation with H₂O₂. Computer simulation supported alteration of one of the two Ca²⁺-binding sites on furin. Taken together, our results implicate that the Ca²⁺-dependent proteolytic activity of this convertase is targeted by H₂O₂, which in turn could contribute to the reduced epidermal expression of the POMC-derived peptides -MSH and β-endorphin as documented earlier in patients with vitiligo.