Cystatin E/M encoded by the CST6 gene is a member of family 2 of the cystatin superfamily. It inhibits papain and cathepsin B, two of the cysteine proteases. Its mRNA was found in many tissues by the two groups who did initial cloning. However, its protein was found only in skin and sweat glands by a third group. In addition to being a cysteine protease inhibitor, cystatin E/M is also a substrate for transglutaminases. It is required for viability and for correct formation of cornified layers in the epidermis and hair follicles, as ichq mice, with a null mutation in the cystatin E/M gene, have defects in epidermal cornification and die between 5 and 12 days of age. Cystatin E/M expression and function may not be limited to cutaneous epithelia. For example, it is found in rat brain and is induced during neuronal cell differentiation.