Caspase-14 protects against epidermal UVB photodamage and water loss

Department for Molecular Biomedical Research, VIB, Technologie Park 927, B-9052, Ghent, Belgium.
Nature Cell Biology (Impact Factor: 20.06). 07/2007; 9(6):666-74. DOI: 10.1038/ncb1597
Source: PubMed

ABSTRACT Caspase-14 belongs to a conserved family of aspartate-specific proteinases. Its expression is restricted almost exclusively to the suprabasal layers of the epidermis and the hair follicles. Moreover, the proteolytic activation of caspase-14 is associated with stratum corneum formation, implicating caspase-14 in terminal keratinocyte differentiation and cornification. Here, we show that the skin of caspase-14-deficient mice was shiny and lichenified, indicating an altered stratum-corneum composition. Caspase-14-deficient epidermis contained significantly more alveolar keratohyalin F-granules, the profilaggrin stores. Accordingly, caspase-14-deficient epidermis is characterized by an altered profilaggrin processing pattern and we show that recombinant caspase-14 can directly cleave profilaggrin in vitro. Caspase-14-deficient epidermis is characterized by reduced skin-hydration levels and increased water loss. In view of the important role of filaggrin in the structure and moisturization of the skin, the knockout phenotype could be explained by an aberrant processing of filaggrin. Importantly, the skin of caspase-14-deficient mice was highly sensitive to the formation of cyclobutane pyrimidine dimers after UVB irradiation, leading to increased levels of UVB-induced apoptosis. Removal of the stratum corneum indicate that caspase-14 controls the UVB scavenging capacity of the stratum corneum.

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Available from: Richard Presland, Jan 14, 2014
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    • "Caspase-14 þ / þ and caspase-14 À / À mice have been described previously (Denecker et al., 2007). Mice were kept under specific pathogen-free conditions, and all procedures were approved by the institutional ethics committee. "
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    ABSTRACT: Caspase-14 is an important protease in the proper formation of a fully functional skin barrier. Newborn mice that are deficient in caspase-14 exhibit increased transepidermal water loss and are highly sensitive to UVB-induced photodamage. Decreased caspase-14 expression and incomplete caspase-14 processing in lesional psoriatic parakeratotic stratum corneum has been reported previously. In this study, we show that caspase-14-deficient skin frequently displays incompletely cornified cells in the transitional zone between the granular and the cornified layers, pointing to a delay in cornification. We also demonstrate that after challenge of epidermal permeability barrier function by repetitive acetone treatment, a higher incidence of large parakeratotic plaques was observed in caspase-14-deficient skin. Furthermore, caspase-14-deficient mice are more prone than control mice to the development of parakeratosis upon induction of psoriasis-like dermatitis by imiquimod treatment. These results show that lack of caspase-14 expression predisposes to the development of parakeratosis and that caspase-14 has an important role in keratinocyte terminal differentiation and the maintenance of normal stratum corneum, especially in conditions causing epidermal hyperproliferation.Journal of Investigative Dermatology advance online publication, 27 September 2012; doi:10.1038/jid.2012.350.
    Journal of Investigative Dermatology 09/2012; 133(3). DOI:10.1038/jid.2012.350 · 6.37 Impact Factor
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    • "Caspase-14 has been found to localize to the nuclear remnants of corneocytes and is associated with the nucleus in the precursor granular layer. Although these findings support the hypothesis that caspase-14 is required for nuclear degradation, caspase-14-deficient mice show no defects in cornification (Denecker et al., 2007). "
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    Cell 11/2011; 147(4):742-58. DOI:10.1016/j.cell.2011.10.033 · 33.12 Impact Factor
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    • "This condensed cytoskeleton functions as a scaffold for the formation of a cornified envelope (Candi et al. 2005). Filaggrin is finally degraded by proteases, such as caspase14 (Denecker et al. 2007), thereby releasing free amino acids that provide essential epidermal hydration (Candi et al. 2005). "
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    ABSTRACT: The skin is the outer layer of protection against the environment. The development and formation of the skin is regulated by several genetic cascades including the bone morphogenetic protein (BMP) signaling pathway, which has been suggested to play an important role during embryonic organ development. Several skin defects and diseases are caused by genetic mutations or disorders. Ichthyosis is a common genetic skin disorder characterized by dry scaly skin. Loss-of-function mutations in the filaggrin (FLG) gene have been identified as the cause of the ichthyosis vulgaris (IV) phenotype; however, the direct regulation of filaggrin expression in vivo is unknown. We present evidence that BMP signaling regulates filaggrin expression in the epidermis. Mice expressing a constitutively active form of BMP-receptor-IB in the developing epidermis exhibit a phenotype resembling IV in humans, including dry flaky skin, compact hyperkeratosis, and an attenuated granular layer associated with a significantly downregulated expression of filaggrin. Regulation of filaggrin expression by BMP signaling has been further confirmed by the application of exogenous BMP2 in skin explants and by a transgenic model overexpressing Noggin in the epidermis. Our results demonstrate that aberrant BMP signaling in the epidermis causes overproliferation and hyperkeratinization, leading to an IV-like skin disease.
    Cell and Tissue Research 11/2010; 342(3):401-10. DOI:10.1007/s00441-010-1077-2 · 3.33 Impact Factor
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