Sang Eun Lee, et al. brane-bound serine protease, prostatin (CAP1/PRSS8), and could activate prostatin in vitro, resulting in the initia- tion of a proteolytic cascade toward ENaC activation.53 Desquamation Desquamation involves the enzymatic process of degrada- tion of corneodesmosomal proteins including corneodes- mosin (CDSN), desmoglein 1 (DSG1), and desmocollin 1 (DSC1). It is well known that KLKs, especially KLK5 and KLK7, act as main players in desquamation through a pH- dependent protease signaling cascade (Fig. 1).20 KLK7 directly cleaves CDSN and DSC1 but is unable to degrade DSG1, while KLK5 can.54 During KLK proteolytic activa- tion cascade, pro-KLK5 is activated by KLK14 and by KLK5 itself, and the active KLK5 then activates pro-KLK7 and pro-KLK14; thus, KLK5 is believed to be the cascade initiator.24 Besides KLK5, -7, and -14, it has been reported that KLK8 is also involved in skin desquamation through a protease cascade reaction leading to the degradation of DSG1 and CDSN.29 Recently, KLK6, -13, and -14 have been found to degrade DSG1 and be inhibited by LEKTI, suggesting that these KLKs are also potential desquama- tory enzymes.54 The desquamation process is tightly con- trolled by the epidermal pH gradient. Skin pH regulates not only the activity of KLK but also the binding of KLK to LEKTI fragments.55 At a neutral pH of the SG-SC junc- tion, KLK is tightly bound to LEKTI fragments, however, with a decrease in pH (acidic pH of the SC) the dissocia- tion of KLK from LEKTI becomes more frequent, releas- ing free KLKs into the outer layer of the SC.55 However, at the acidic pH of the superficial SC layer, KLKs exhibit lower activity than at a neutral pH. This bidirectional regulation of KLKs and their inhibitors by pH is important to maintain proper skin desquamation.13 In addition to serine proteases, cystein protease, cathepsin V, and cysta- tin M/E, an inhibitor of asparaginyl endopeptidase legu- main (LGMN) and cysteine proteases also controls desqua- mation.56,57 Cathepsin V has been known to degrade DSG1, DSC1, and CDSN with a higher proteolytic activity at an acidic pH, suggesting that cathepsin V is a major player in desquamation under basal conditions with a normal SC acidic pH.56 Cystatin M/E regulates desquamation by inhi- bition of cathepsin V as well as LGMN, which regulates pH-dependent processing of (pro)-cathepsins. In addition, cystatin M/E regulates crosslinking of structural proteins by transglutaminase (TGM) 3 during epidermal differen- tiation by controlling cathepsin L and LGMN activities.56 A recent study has shown that the cystatin M/E and cathep- sin V were expressed to a lesser degree in lesional skin of AD, suggesting that disturbance of the cystatin M/E- cathepsin pathway could contribute to abnormal skin barrier function in AD.58 Degradation of lipid processing enzyme The permeability barrier function of the SC is provided by lipid bilayers and corneocytes. The lamellate structure of SC intercellular lipids is formed by the delivery of lipid precur- sors to the SG-SC junction by LBs and the proper process- ing of these precursors by their extracellular processing enzymes. It has been demonstrated that serine proteases have a central role in the formation and maintenance of the epidermal lipid barrier by degrading the key lipid processing enzymes required for normal permeability barrier homeos- tasis and PAR-2-mediated manipulating LB secretion (Fig. 1).7,21 Hachem, et al.21 reported that increased serine protease activity provoked by sustained SC neutralization with super- Fig. 2. Role of PAR-2 in the epidermal permeability barrier homeostasis. LB, lamellar body; PAR-2, protease-activated receptor-2. 812 Yonsei Med J http://www.eymj.org Volume 51 Number 6 November 2010