Regulation of kallikrein-related peptidases in the skin – from physiology to diseases to therapeutic options

Abstract

SummaryKallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases, which show a tissue-specific expression profile. This made them valuable tumour expression markers. It became evident that KLKs are involved in many physiological processes like semen liquefaction and skin desquamation. More recently, we have learnt that they are involved in many pathophysiological conditions and diseases making them promising target of therapeutic intervention. Therefore, regulation of KLKs raised the interest of numerous reports. Herein, we summarise the current knowledge on KLKs regulation with an emphasis on skin-relevant KLKs regulation processes.Regulation of KLKs takes place on the level of transcription, on protease activation and on protease inactivation. A variety of protease inhibitors has been described to interact with KLKs including the irreversible serine protease inhibitors (SERPINs) and the reversible serine protease inhibitors of Kazal-type (SPINKs). In an attempt to integrate current knowledge, we propose that KLK regulation has credentials as targets for therapeutic intervention.

Kallikreins – The melting pot of activity and function

“…Serpins target almost exclusively proteases of the S1 family and are certainly involved in control of kallikrein activity [14]. Although serpins, as exemplified by α1-antitrypsin [15], have a long history of therapeutic use and are the best studied inhibitors for kallikreins [16–18], it is unlikely that they can be used in therapies targeting single kallikreins. Interestingly, α 2 -macroglobulin (α 2 M), a serum derived pan-proteinase inhibitor that clears proteases destined for degradation from the blood, can control the activity of only KLK1, KLK2, and KLK3.…”

Specificity studies on Kallikrein-related peptidase 7 (KLK7) and effects of osmolytes and glycosaminoglycans on its peptidase activity

“…KLK7 was earlier named stratum corneum chymotryptic enzyme (SCCE) [7,8] due to its skin source and characteristics of a serine protease with preference for hydrolysis after Y or F amino acid residues. KLK7 was reported to be involved in skin inflammation [9], in the proteolytic regulation of the antimicrobial effects of cathelicidins in skin [10] and in the skin desquamation process [11][12][13]. Tissue extracts of esophagus, liver, salivary glands and heart have high concentrations of KLK7 [14,15].…”

“…KLK7 plays roles in physiological and pathological skin desquamation processes [37][38][39][40][41] that requires the presence of water in the stratum corneum, which is maintained by hygroscopic compounds collectively named as skin moisturizing factor [42,43]. Its chemical composition, besides the regular salts, includes free amino acids from the proteolytic degradation of filaggrin.…”

Staphylococcal Biofilms in Atopic Dermatitis

“…These proteases act to degrade superfluous proteins, activate downstream pathways that impact terminal differentiation, and cleave precursors of structural proteins or other proteases into mature, processed versions [31]. Given the tight regulation of skin barrier function by the balance between critical proteases such as the kallikreins and protease inhibitors such as SPINK5, it is no surprise that changes in protease levels or activity in the skin contribute to defects in barrier function seen in AD [32–35]. Recently, filaggrin knockdown keratinocytes were shown to have increased endogenous cysteine protease activity, suggesting that the epidermal phenotype observed in FLG deficiency may be due in part to unleashed cysteine protease activity.…”

“…For example, S. aureus induces increased secretion of kallikreins by keratinocytes [37]. These serine proteases can act to degrade filaggrin as well as desmoglein-1, an important component of desmosomes [32, 37]. Cleavage of desmoglein-1 is a normal aspect of desquamation, but dysregulation of this process can lead to impaired barrier function.…”