Denecker G, Hoste E, Gilbert B et al.Caspase-14 protects against epidermal UVB photodamage and water loss. Nat Cell Biol 9:666-674

Department for Molecular Biomedical Research, VIB, Technologie Park 927, B-9052, Ghent, Belgium.
Nature Cell Biology (Impact Factor: 19.68). 07/2007; 9(6):666-74. DOI: 10.1038/ncb1597
Source: PubMed


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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    • "Casp14 belongs to a conserved family of aspartate-specific proteinases. It is expressed in the suprabasal layers of the epidermis and is associated with protection against UVB-induced apoptosis and water loss [29], [30]. In the mouse mucosal LCM samples, radiation injury induced a 67-fold increase of Casp14 mRNA at 4 h, 33-fold at 24 h, and then rapidly returned to the baseline at 3.5 d. "
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    ABSTRACT: The intestinal mucosa is the compartment that sustains the most severe injury in response to radiation and is therefore of primary interest. The use of whole gut extracts for analysis of gene expression may confound important changes in the mucosa. On the other hand, laser capture microdissection (LCM) is hampered by the unstable nature of RNA and by a more complicated collection process. This study assessed, in parallel samples from a validated radiation model, the indications for use of LCM for intestinal gene expression analysis. RNA was extracted from mouse whole intestine and from mucosa by LCM at baseline and 4 h, 24 h, and 3.5 d after total body irradiation and subjected to microarray analysis. Among mucosal genes that were altered > = 2-fold, less than 7% were present in the whole gut at 4 and 24 h, and 25% at 3.5 d. As expected, pathway analysis of mucosal LCM samples showed that radiation activated the coagulation system, lymphocyte apoptosis, and tight junction signaling, and caused extensive up-regulation of cell cycle and DNA damage repair pathways. Using similar stringent criteria, regulation of these pathways, with exception of the p53 pathway, was undetectable in the whole gut. Radiation induced a dramatic increase of caspase14 and ectodysplasin A2 receptor (Eda2r), a TNFα receptor, in both types of samples. LCM-isolated mucosal specimens should be used to study cellular injury, cell cycle control, and DNA damage repair pathways. The remarkable increase of caspase14 and Eda2r suggests a novel role for these genes in regulating intestinal radiation injury. Comparative gene expression data from complex tissues should be interpreted with caution.
    PLoS ONE 01/2013; 8(1):e53711. DOI:10.1371/journal.pone.0053711 · 3.23 Impact Factor
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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 · 7.22 Impact Factor
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    • "It is expressed in the granular layer of epidermis and consists of a unique N-terminal domain; a region with multiple FLG repeats; and a unique C-terminal end domain.13,14 During terminal differentiation at the granular to cornified cell transition, profilaggrin is rapidly dephosphorylated and cleaved by several endoproteases including caspase-14, to generate FLG and the N-terminal domain.13,17,18 FLG aggregates the keratin filaments into tight bundles.13,14 "
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    ABSTRACT: Atopic dermatitis (AD) is a complex disease that affects up to 20% of children and impacts the quality of patients and families in a significant manner. New insights into the pathophysiology of AD point to an important role of structural abnormalities in the epidermis combined with immune dysregulation. Filaggrin (FLG) is synthesized as a large precursor, profilaggrin, and is expressed in the upper layers of the epidermis. FLG plays a critical role in the epidermal barrier, and FLG mutations cause abnormal epidermal function. FLG mutations are strongly associated with early-onset, and persistent severe AD. In addition, FLG deficiency in the epidermis is related to allergic sensitization and asthma. The basic skin care including repair and protection of the skin barrier with proper hydration and topical anti-inflammatory therapy is important to control the severity of skin disease in patients with AD.
    Allergy, asthma & immunology research 01/2012; 4(1):12-6. DOI:10.4168/aair.2012.4.1.12 · 2.43 Impact Factor
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