A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. [J Biol Chem] Journal article

Desquamation of the stratum corneum is a serine protease dependent process. Two members of the human tissue kallikrein (KLK) family of (chymo)tryptic-like serine proteases, KLK5 and KLK7, are implicated in desquamation by digestion of (corneo)desmosomes and inhibition by desquamation-related serine protease inhibitors (SPI). However, the epidermal localization and specificity of additional KLKs also supports a role for these enzymes in desquamation. This study aims to delineate the probable contribution of KLK1, KLK5, KLK6, KLK13 and KLK14 to desquamation by examining their interactions, in vitro, with: 1) co-localized SPI, lympho-epithelial Kazal-type related inhibitor [LEKTI; 4 recombinant fragments containing inhibitory domains 1-6, rLEKTI(1-6); 6-8 and partial domain 9, rLEKTI(6-9'); 9-12, rLEKTI(9-12) and 12-15, rLEKTI(12-15)], secretory leukocyte protease inhibitor (SLPI) and elafin and 2) their ability to digest the (corneo)desmosomal cadherin, desmoglein 1 (DSG1). KLK1 was not inhibited by any SPI tested. KLK5, KLK6, KLK13 and KLK14 were potently inhibited by rLEKTI(1-6), rLEKTI(6-9') and rLEKTI(9-12) with Ki values in the range of 2.3-28.4 nM, 6.1-221 nM and 2.7-416 nM for each respective fragment. Only KLK5 was inhibited by rLEKTI(12-15) (Ki = 21.8 nM). No KLK was inhibited by SLPI or elafin. Apart from KLK13, all KLKs digested the ectodomain of DSG1 within cadherin repeats, Ca2+ binding sites or in the juxtamembrane region. Our study indicates that multiple KLKs may participate in desquamation through cleavage of desmoglein 1 and regulation by LEKTI. These findings may have clinical implications for the treatment of skin disorders in which KLK activity is elevated.

J Biol Chem