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Review
. 2008 Feb 11;180(3):451-8.
doi: 10.1083/jcb.200709098. Epub 2008 Feb 4.

Caspase-14 reveals its secrets (VSports手机版)

Geertrui Denecker  1 , Petra Ovaere, Peter Vandenabeele, Wim Declercq
Affiliations
Review

Caspase-14 reveals its secrets

Geertrui Denecker et al. J Cell Biol. .

Abstract

Caspase-14 is a unique member of the evolutionarily conserved family of cysteinyl aspartate-specific proteinases, which are mainly involved in inflammation and apoptosis. However, recent evidence also implicates these proteases in proliferation and differentiation. Although most caspases are ubiquitously expressed, caspase-14 expression is confined mainly to cornifying epithelia, such as the skin. Moreover, caspase-14 activation correlates with cornification, indicating that it plays a role in terminal keratinocyte differentiation VSports手机版. The determination of in vitro conditions for caspase-14 activity paved the way to identifying its substrates. The recent development of caspase-14-deficient mice underscored its importance in the correct degradation of (pro)filaggrin and in the formation of the epidermal barrier that protects against dehydration and UVB radiation. Here, we review the current knowledge on caspase-14 in skin homeostasis and disease. .

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Figures

Figure 1.
Figure 1.
General structure of the epidermis. See Introduction for details.
Figure 2.
Figure 2.
Alignment of the currently known procaspase-14 amino acid sequences. Sequence analysis indicates that a hydrophobic patch in the protease-sensitive loop is conserved. Only part of the alignment is shown here, including the C-terminal part of the p20 subunit, the protease-sensitive loop, and the N-terminal part of the p10 subunit. The darker the yellow, the more the amino acids are conserved between species. The catalytic QACRG box is delineated with a green box. The conserved hydrophobic patch is delineated with a red box, and the cleavage site in human caspase-14 is indicated with a red arrow. The alignment was performed using ClustalW (Mega version 3.1; Kumar et al., 2004) and was manually optimized in the protease-sensitive loop region. JalView 2.3 (Clamp et al., 2004) was used for visualization.
Figure 3.
Figure 3.
Expression of caspase-14 and (pro)filaggrin in wild-type and caspase-14–deficient skin. Immunofluorescence staining for caspase-14 (red) and (pro)filaggrin (green) on paraffin sections of 5.5-d-old skin of both wild-type (+/+) and caspase-14–deficient (−/−) mice (Denecker et al., 2007). Nuclei are counterstained with DAPI. Fluorescence microscopy was performed on a CellM system (Olympus) with an upright microscope (BX61; Olympus). Observation was performed with a 60× 1.42 NA oil objective. A specific DAPI emission band-pass filter (450–470 nm) and a GFP emission band-pass filter (510–550 nm) were used. Image acquisition and processing were performed with the CellM software using a cooled CCD camera with a 1,344 × 1,024 pixel resolution. Image intensity scaling and color conversion were completed in ImageJ (National Institutes of Health). The dotted lines indicate the outer borders of the stratum corneum. Caspase-14 is expressed mainly in the spinous, granular, and cornified layers of wild-type mice and is absent in caspase-14–deficient mice. (Pro)filaggrin is expressed in the granular layer and in the lower cornified layer in wild-type skin. In caspase-14–deficient skin, additional filaggrin immunoreactive fragments are detected in the upper layers of the stratum corneum.
Figure 4.
Figure 4.
Caspase-14 protects the skin against UVB photo damage and water loss and is involved in the processing of (pro)filaggrin. Caspase-14 expression starts in the spinous layer (indicated in shades of red), and cleavage into its p20 and p10 subunits occurs at the transition of the granular to the cornified layer. Caspase-14 is active in the dehydrating environment of the cornified layer, where it has an important function in formation of the epidermal barrier leading to protection against UVB and water loss (Denecker et al., 2007). Profilaggrin is a large structural molecule consisting of an N-terminal A domain and a B domain followed by multiple filaggrin repeats and a unique C-terminal sequence (for review see Candi et al., 2005). Profilaggrin undergoes many posttranslational modifications, eventually leading to release from the keratin intermediate filaments (see the section on the function of caspase-14 for details). In the lower stratum corneum, dehydration triggers the degradation of filaggrin monomers into free hygroscopic amino acids. These amino acids compose ∼40% of the natural moisturizing factors present in the stratum corneum and are important for maintaining epidermal hydration (Rawlings and Matts, 2005). In caspase-14–deficient skin, accumulating filaggrin fragments are present (Denecker et al., 2007), indicating that an unidentified protease (asterisk) cleaves the filaggrin monomer into these fragments and that caspase-14 is responsible for the further processing and degradation of these fragments into free amino acids. As it is very unlikely that caspase-14 is directly responsible for degradation of the filaggrin fragments into free amino acids, we propose two possible mechanisms: (1) caspase-14 could first cleave these filaggrin fragments, leading to further degradation into free amino acids by another endo- and/or exopeptidase; or (2) caspase-14 could directly or indirectly (by inactivating an inhibitor) activate an endo- and/or exopeptidase that further processes the smaller filaggrin fragments. KG, keratohyalin granule; KIF, keratin intermediate filament; NMF, natural moisturizing factors; SB, stratum basale; SC, stratum corneum; SG, stratum granulosum; SS, stratum spinosum; TG, transglutaminase.
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