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

Abstract

The Ca(2+)-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, beta-lipotropin, and beta-endorphin. All prohormone convertases including furin are regulated by Ca(2+). Because numerous epidermal peptides and enzymes are affected by H(2)O(2)-mediated oxidation, including the POMC-derived peptides alpha-MSH and beta-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, Ca(2+)-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 H(2)O(2)-mediated oxidation. This was confirmed by (45)Ca(2+)-binding studies with human recombinant furin identifying the loss of one Ca(2+)-binding site from the enzyme after oxidation with H(2)O(2). Computer simulation supported alteration of one of the two Ca(2+)-binding sites on furin. Taken together, our results implicate that the Ca(2+)-dependent proteolytic activity of this convertase is targeted by H(2)O(2), which in turn could contribute to the reduced epidermal expression of the POMC-derived peptides alpha-MSH and beta-endorphin as documented earlier in patients with vitiligo.

6-Shogaol Protects Human Melanocytes against Oxidative Stress through Activation of the Nrf2-Antioxidant Response Element Signaling Pathway

“…In vitiligo, H 2 O 2 was reported to oxidize melanogenesis-related hormones and factors, such as epidermal ACTH, α-MSH, and β-endorphin, resulting in the loss of their functions via the promotion of pigmentation in melanocytes [37]. Furthermore, H 2 O 2 -mediated oxidation is also reported to affect calcium binding, disrupting calcium homeostasis and l-phenylalanine-uptake in the epidermis in acute vitiligo [38]. In addition, impaired Nrf2 signaling, decreased antioxidative enzyme levels, including HO-1, and increased oxidative stress have been reported in patients with vitiligo [39][40][41][42].…”

An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth

“…The prevalence of unprocessed ADAM10 in tumors has not previously been reported, and the cause is unknown; however, reduced processing of other membrane-bound proteins and altered activity of pro-protein convertases are known to occur in cancer cells (Sadeqzadeh et al, 2011; Huang et al, 2012; Demidyuk et al, 2013). Indeed, inhibited processing may also be ROS related, as oxidation of furin disrupts its calcium-binding capacity, resulting in defective activity (Spencer et al, 2008). Thus, high ROS levels may result in coincident activation of ADAM10 with inhibition of its processing by furin, rather than activity being directly dependent on processing.…”

Decreased methionine sulphoxide reductase A expression renders melanocytes more sensitive to oxidative stress: a possible cause for melanocyte loss in vitiligo

“…14 Several exogenous and endogenous sources for H 2 O 2 accumulation have been confirmed. 15 Compared with keratinocytes, melanocytes show lower antioxidant enzyme activities, which makes them a good target for H 2 O 2 . 16 Fortunately, melanocytes possess MSRA, MSRB and thioredoxin reductase.…”