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.
Hagemann
Sascha
S
Institut für Molekulare Medizin und Zellforschung, Universität Freiburg, Freiburg, Germany.
Günther
Thomas
T
Dennemärker
Julia
J
Lohmüller
Tobias
T
Brömme
Dieter
D
Schüle
Roland
R
Peters
Christoph
C
Reinheckel
Thomas
T
D000818:Animals; D056668:Cathepsin L; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004817:Epidermis / Q000201:enzymology*; D005816:Genetic Complementation Test; D018859:Hair Follicle / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D053547:Keratin-14; D007633:Keratins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010802:Phylogeny; D011401:Promoter Regions, Genetic / Q000235:genetics
C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; D007633:Keratins; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C117627:CTSV protein, human