Kallikrein‐mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin

Abstract

The presence of cathelicidin antimicrobial peptides provides an important mechanism for prevention of infection against a wide variety of microbial pathogens. The activity of cathelicidin is controlled by enzymatic processing of the proform (hCAP18 in humans) to a mature peptide (LL-37 in human neutrophils). In this study, elements important to the processing of cathelicidin in the skin were examined. Unique cathelicidin peptides distinct from LL-37 were identified in normal skin. Through the use of selective inhibitors, SELDI-TOF-MS, Western blot, and siRNA, the serine proteases stratum corneum tryptic enzyme (SCTE, kallikrein 5) and stratum corneum chymotryptic protease (SCCE, kallikrein 7) were shown to control activation of the human cathelicidin precursor protein hCAP18 and also influence further processing to smaller peptides with alternate biological activity. The importance of this serine protease activity to antimicrobial activity in vivo was illustrated in SPINK5-deficient mice that lack the serine protease inhibitor LEKTI. Epidermal extracts of these animals show a significant increase in antimicrobial activity compared with controls, and immunoabsorption of cathelicidin diminished antimicrobial activity. These observations demonstrate that the balance of proteolytic activity at an epithelial interface will control innate immune defense.

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

“…KLK5, KLK7, and KLK14 contribute to desquamation by degrading desmosomal cad herins such as desmoglein 1 and desmocollin 1 (Caubet et al, 2004;Fortugno et al, 2011) whereas caspase 14 is needed to complete the processing of filaggrin (Flg; Denecker et al, 2007;Hoste et al, 2011). KLK5 and KLK14 are also able to stimulate proinflammatory and proallergic signals via protease activated receptor 2 (PAR2; Stefansson et al, 2008;Briot et al, 2009) and KLK5 and KLK7 are linked to the maturation of cathelicidin antimicrobial peptides (Yamasaki et al, 2006). Thus, LEKTI coordinates the timing of several important proteolytic events in epidermal physiology and its absence in NS causes dysregulation of multiple pathways.…”

Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance

“…The regulated tissue-specifi c expression and activation of KLKs enable them to participate in a great number of diverse physiological procedures, such as the regulation of blood pressure (KLK1-mediated cleavage of kininogenase) (Bhoola et al , 1992 ), semen liquefaction (PSA/KLK3-and KLK2-mediated cleavage of semenogelins) (Pampalakis and Sotiropoulou , 2007 ), skin desquamation (KLK5-, KLK7-, and KLK14-mediated digestion of desmoglein, desmocollin, corneodesmosin) (Borgono et al , 2007a ), tooth maturation (KLK4-mediated processing of enamelin) (Lu et al , 2008 ), and innate immunity (KLK5-and KLK7-mediated activation of cathelicidin antimicrobial peptide) (Yamasaki et al , 2006 ). Bearing in mind the irreversible impact of proteases upon their substrates, as well as the launch of downstream enzyme cascades that lead to the amplifi cation of the initial stimuli, the regulation of KLKs activity becomes crucial for their benefi cial physiological function.…”

Human Kallikrein-related Peptidase 14 (KLK14) Is a New Activator Component of the KLK Proteolytic Cascade

“…ably through a cascade-mediated cleavage of the cathelicidin precursor, hCAP18 (human cationic antimicrobial protein 18), to its antimicrobial active form (LL-37) (18).…”