The human cysteine protease cathepsin V can compensate for murine cathepsin L in mouse epidermis and hair follicles

Mice lacking the ubiquitously expressed lysosomal cysteine protease Cathepsin L, show a complex skin phenotype consisting of periodic hair loss and epidermal hyperplasia with hyperproliferation of basal epidermal keratinocytes, acanthosis and hyperkeratosis. The recently identified human Cathepsin L-like enzyme Cathepsin V, which is also termed Cathepsin L2, is specifically expressed in cornea, testis, thymus, and epidermis. To date, in mice no Cathepsin V orthologue with this typical expression pattern has been identified. Since Cathepsin V has about 75% protein sequence identity to murine Cathepsin L, we hypothesized that transgenic, keratinocyte-specific expression of Cathepsin V in Cathepsin L knockout mice might rescue the skin and hair phenotype. Thus, we generated a transgenic mouse line expressing Cathepsin V under the control of the human keratin 14 promoter, which mimics the genuine Cathepsin V expression pattern in human skin, by directing it to basal epidermal keratinocytes and the outer root sheath of hair follicles. Subsequently, transgenic mice were crossed with congenic Cathepsin L knockout Animals. The resulting mice show normalization of epidermal proliferation and normal epidermal thickness as well as rescue of the hair phenotype. These findings provide evidence for keratinocyte-specific pivotal functions of Cathepsin L-like proteolytic activities in maintenance of epidermis and hair follicles and suggest, that Cathepsin V may perform similar functions in human skin.