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.
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ABSTRACT: Abstract The innate immune system represents the first line of defense against infectious agents, and co-ordinates cellular and molecular mechanisms that result in effective inflammatory and anti-microbial responses against pathogens. Infection and cellular stress trigger assembly of canonical and non-canonical inflammasome complexes that activate the inflammatory caspases-1 and -11, respectively. These inflammatory caspases play key roles in innate immune responses by inducing pyroptosis to halt intracellular replication of pathogens, and by engaging the extracellular release of pro-inflammatory cytokines and danger signals. In addition, the inflammatory caspases-4, -5 and -11 were recently shown to directly bind microbial components. Although the immune roles of caspase-12 are debated, it was proposed to dampen inflammatory responses by interfering with caspase-1 activation and other innate immune pathways. Here, we recapitulate the reported roles of inflammatory caspases with an emphasis on recent insights into their biological functions.Biological Chemistry 11/2014; 396(3). DOI:10.1515/hsz-2014-0253 · 2.69 Impact Factor
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ABSTRACT: Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase-3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases.Cell Death and Differentiation advance online publication, 19 December 2014; doi:10.1038/cdd.2014.216.Cell Death and Differentiation 12/2014; 22(4). DOI:10.1038/cdd.2014.216 · 8.39 Impact Factor
Article: Cell Death in Genome Evolution.[Show abstract] [Hide abstract]
ABSTRACT: Inappropriate survival of abnormal cells underlies tumorigenesis. Most discoveries about programmed cell death have come from studying model organisms. Revisiting the experimental contexts that inspired these discoveries helps explain confounding biases that inevitably accompany such discoveries. Amending early biases has added a newcomer to the collection of cell death models. Analysis of gene-dependent death in yeast revealed the surprising influence of single gene mutations on subsequent eukaryotic genome evolution. Similar events may influence the selection for mutations during early tumorigenesis. The possibility that an early random mutation might drive the selection for a cancer driver mutation is conceivable but difficult to demonstrate. This was tested in yeast, revealing that mutation of almost any gene appears to specify the selection for a new second mutation. Some human tumors contain pairs of mutant genes homologous to co-occurring mutant genes in yeast. Here we consider how yeast again provide novel insights into tumorigenesis. Copyright © 2015. Published by Elsevier Ltd.Seminars in Cell and Developmental Biology 02/2015; 39. DOI:10.1016/j.semcdb.2015.02.014 · 5.97 Impact Factor