The biology of cystatin ME and its cognate target proteases

Abstract

Cystatin ME is a member of a superfamily of evolutionarily-related cysteine protease inhibitors that provide regulatory and protective functions against uncontrolled proteolysis by cysteine proteases. Although most cystatins are ubiquitously expressed, high levels of cystatin ME expression are mainly restricted to the epithelia of the skin (epidermis, hair follicles, sebaceous glands, and sweat glands) and to a few extracutaneous tissues. The identification of its physiological targets and the localization of these proteases in skin have suggested a regulatory role for cystatin ME in epidermal differentiation. In vitro biochemical approaches as well as the use of in vivo mouse models have revealed that cystatin ME is a key molecule in a biochemical pathway that controls skin barrier formation by the regulation of both crosslinking and desquamation of the stratum corneum. Cystatin ME directly controls the activity of cathepsin V, cathepsin L, and legumain, thereby regulating the processing of transglutaminases. Misregulation of this pathway by unrestrained protease activity, as seen in cystatin ME-deficient mice, leads to abnormal stratum corneum and hair follicle formation, as well as to severe disturbance of skin barrier function. Here, we review the current knowledge on cystatin ME in skin barrier formation and its potential role as a tumor suppressor gene.