The biology of cystatin M/E and its cognate target proteases.
Cystatin M/E 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 M/E 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 M/E in epidermal differentiation. In vitro biochemical approaches as well as the use of in vivo mouse models have revealed that cystatin M/E 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 M/E 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 M/E-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 M/E in skin barrier formation and its potential role as a tumor suppressor gene.
Zeeuwen
Patrick L J M
PL
Department of Dermatology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. p.zeeuwen@ncmls.ru.nl
Cheng
Tsing
T
Schalkwijk
Joost
J
D000818:Animals; D055332:Cystatin M / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D018859:Hair Follicle / Q000378:metabolism; D006801:Humans; D007057:Ichthyosis / Q000235:genetics; D007249:Inflammation; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010447:Peptide Hydrolases / Q000378:metabolism*
D055332:Cystatin M; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases