Caspase-14 protects against epidermal UVB photodamage and water loss

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.

Old, new and emerging functions of caspases

“…99,100 Caspase-14 was found to be involved in cornification, hydration and protection against UVB by correct processing and degradation of (pro)filaggrin. 101 In addition to caspase-14, caspase-3 functions in the commitment stage of embryonic keratinocytes to terminal differentiation. 102 During keratinocyte differentiation, caspase-3 activity is induced following Notch1 signaling and mediates cleavage and activation of PKC-d, a positive regulator of keratinocyte differentiation.…”

No death without life: vital functions of apoptotic effectors

“…39 Caspase-14 À/À mice exhibit an altered composition of the stratum corneum, presumably due to an aberrant processing of filaggrin. 40 This results in reduced skin-hydration levels and enhanced sensitivity of the skin to UVB-induced photodamage and apoptosis. 40 Altogether, these examples (Table 1) illustrate that most if not all caspases have cell death-unrelated functions.…”

“…40 This results in reduced skin-hydration levels and enhanced sensitivity of the skin to UVB-induced photodamage and apoptosis. 40 Altogether, these examples (Table 1) illustrate that most if not all caspases have cell death-unrelated functions.…”

Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome

“…Collectively, these proteases are known to hold prominent roles in the SC. KLK5, KLK7, and KLK14 contribute to desquamation by degrading desmosomal cad herins such as desmoglein 1 and desmocollin 1 (Caubet et al, 2004;Fortugno et al, 2011) whereas caspase 14 is needed to complete the processing of filaggrin (Flg; Denecker et al, 2007;Hoste et al, 2011). KLK5 and KLK14 are also able to stimulate proinflammatory and proallergic signals via protease activated receptor 2 (PAR2; Stefansson et al, 2008;Briot et al, 2009) and KLK5 and KLK7 are linked to the maturation of cathelicidin antimicrobial peptides (Yamasaki et al, 2006).…”