Proteolytic activation of prochemerin by kallikrein 7 breaks an ionic linkage and results in C-terminal rearrangement

Abstract

The excessive accumulation of adipose tissue in obesity is associated with multiple inflammatory dermatological diseases. Chemerin, a chemoattractant adipokine, dependent on proteolytical activation, is highly expressed in skin. Different proteases have been reported to activate prochemerin, but none is inherently expressed in human skin. In the present study, we identified a tissue-specific protease and investigated the underlying mechanism of activation at the molecular level. We characterized human KLK7 (kallikrein 7) as a prochemerin processing protease in vitro converting prochemerin into active chemerinF(156). The activating truncation by the protease might trigger a structural rearrangement leading to an increased affinity of chemerin to CMKLR1 (chemokine-like receptor 1). Molecular modelling and experimental data suggest an underlying ionic interaction in prochemerin C-terminal domains. These findings provide a general molecular basis for the necessity of C-terminal processing of prochemerin. Moreover, immunohistochemistry was used to investigate prochemerin, KLK7 and the recently identified KLK7 inhibitor vaspin expression in human skin biopsies, and distinct co-localization in psoriatic biopsies was observed. On the basis of these results, it is hypothesized that KLK7 activity may contribute to the development of psoriatic lesions as a consequence of excessive chemerin activation and impaired protease activity regulation by vaspin. Therefore this interaction represents an interesting target for psoriasis therapy and treatment of other obesity-related diseases.

Chemerin: A comprehensive review elucidating the need for cardiovascular research

“…With this information, chemerin was hypothesized to be linked to psoriasis through pDCs, which was later supported by data showing increased expression in early lesions, especially in fibroblasts [54]. The association of high chemerin levels with psoriatic lesions has been further supported [55] with some expanding upon the method with which chemerin becomes active in the human skin [56]. This trend of elevated chemerin in epithelial lesions holds true for both Crohn's disease and ulcerative colitis [57] so it is possible that at the discovery of chemerin, scientists mistook prochemerin for the active form.…”

Expression of Human Skin-Specific Genes Defined by Transcriptomics and Antibody-Based Profiling

“…Additional highly expressed genes that were skin enriched were related to melanin production, including melan-A (MLANA), tyrosinase (TYR) and dopachrome tautomerase (DCT). Also in the list of genes enriched in skin were less-well characterized genes, including SERPINA12, which was earlier shown to be linked to the inhibition of the kalkrein-related peptidase, KLK7, in the development of psoriasis (Schultz et al 2013), and interleukin IL37, which was shown to be associated to atopic dermatitis (Kimura et al 2013). The most highly expressed gene in the skin enriched group was the poorly characterized C1orf68 gene, which encodes for the skinspecific protein 32 (synonyms: LEP7, xp32) located within the epidermal differentiation complex together with other skin-specific genes, including the late cornified envelope proteins (Toulza et al 2007;Zhao and Elder 1997).…”

Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

“…In endothelial and vascular smooth muscle cells, multiple studies demonstrated anti-apoptotic (8), anti-inflammatory (9), and anti-migratory (10) effects of vaspin, suggesting a protective role in the pathogenesis of atherosclerosis. In skin, vaspin expression by keratinocytes suppresses the expression and release of inflammatory cytokines by immune cells (11) and possibly regulates the activation of proinflammatory cytokines, such as chemerin, via KLK7 (12). Whereas vaspin-mediated improvement of glucose tolerance and reduction of food intake were found to be dependent on protease inhibition (4,13), anti-inflammatory effects in the liver have been linked to interaction with a membrane-associated endoplasmic reticulum chaperone protein (5).…”