Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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 follicles1,2,3,4. Moreover, the proteolytic activation of caspase-14 is associated with stratum corneum formation, implicating caspase-14 in terminal keratinocyte differentiation and cornification5,6. 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Histomorphological characterization of caspase-14-deficient epidermis.
Figure 2: Caspase-14 mediates profilaggrin processing, and controls transepidermal water loss and stratum corneum hydration.
Figure 3: Caspase-14-deficient mice are highly sensitive to UVB-induced apoptosis.
Figure 4: The UVB-filtering capacity of the stratum corneum is reduced in caspase-14-deficient mice.

Similar content being viewed by others

References

  1. Eckhart, L. et al. Terminal differentiation of human keratinocytes and stratum corneum formation is associated with caspase-14 activation. J. Invest. Dermatol. 115, 1148–1151 (2000).

    Article  CAS  Google Scholar 

  2. Lippens, S. et al. Epidermal differentiation does not involve the pro-apoptotic executioner caspases, but is associated with caspase-14 induction and processing. Cell Death Differ. 7, 1218–1224 (2000).

    Article  CAS  Google Scholar 

  3. Lippens, S. et al. Vitamin D3 induces caspase-14 expression in psoriatic lesions and enhances caspase-14 processing in organotypic skin cultures. Am. J. Pathol. 165, 833–841 (2004).

    Article  CAS  Google Scholar 

  4. Fischer, H. et al. Stratum corneum-derived caspase-14 is catalytically active. FEBS Lett. 577, 446–450 (2004).

    Article  CAS  Google Scholar 

  5. Candi, E., Schmidt, R. & Melino, G. The cornified envelope: a model of cell death in the skin. Nature Rev. Mol. Cell Biol. 6, 328–340 (2005).

    Article  CAS  Google Scholar 

  6. Lippens, S., Denecker, G., Ovaere, P., Vandenabeele, P. & Declercq, W. Death penalty for keratinocytes: apoptosis versus cornification. Cell Death Differ. 12, 1497–1508 (2005).

    Article  CAS  Google Scholar 

  7. Rendl, M. et al. Caspase-14 expression by epidermal keratinocytes is regulated by retinoids in a differentiation-associated manner. J. Invest. Dermatol. 119, 1150–1155 (2002).

    Article  CAS  Google Scholar 

  8. Mikolajczyk, J., Scott, F. L., Krajewski, S., Sutherlin, D. P. & Salvesen, G. S. Activation and substrate specificity of caspase-14. Biochemistry 43, 10560–10569 (2004).

    Article  CAS  Google Scholar 

  9. Lippens, S. et al. Caspase-14 is expressed in the epidermis, the choroid plexus, the retinal pigment epithelium and thymic Hassall's bodies. Cell Death Differ. 10, 257–259 (2003).

    Article  CAS  Google Scholar 

  10. Alibardi, L., Dockal, M., Reinisch, C., Tschachler, E. & Eckhart, L. Ultrastructural localization of caspase-14 in human epidermis. J. Histochem. Cytochem. 52, 1561–1574 (2004).

    Article  CAS  Google Scholar 

  11. Matsuki, M. et al. Defective stratum corneum and early neonatal death in mice lacking the gene for transglutaminase 1 (keratinocyte transglutaminase). Proc. Natl Acad. Sci. USA 95, 1044–1049 (1998).

    Article  CAS  Google Scholar 

  12. Smith, F. J. et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nature Genet. 38, 337–342 (2006).

    Article  CAS  Google Scholar 

  13. Presland, R. B. et al. Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris. J. Invest. Dermatol. 115, 1072–1081 (2000).

    Article  CAS  Google Scholar 

  14. Scott, I. R. & Harding, C. R. Filaggrin breakdown to water binding compounds during development of the rat stratum corneum is controlled by the water activity of the environment. Dev. Biol. 115, 84–92 (1986).

    Article  CAS  Google Scholar 

  15. Presland, R. B. et al. Evidence for specific proteolytic cleavage of the N-terminal domain of human profilaggrin during epidermal differentiation. J. Invest. Dermatol. 108, 170–178 (1997).

    Article  CAS  Google Scholar 

  16. Palmer, C. N. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature Genet. 38, 441–446 (2006).

    Article  CAS  Google Scholar 

  17. Fischer, H. et al. Caspase-14 but not caspase-3 is processed during the development of fetal mouse epidermis. Differentiation 73, 406–413 (2005).

    Article  CAS  Google Scholar 

  18. Hardman, M. J., Sisi, P., Banbury, D. N. & Byrne, C. Patterned acquisition of skin barrier function during development. Development 125, 1541–1552 (1998).

    CAS  Google Scholar 

  19. Lu, Y. P., Lou, Y. R., Peng, Q. Y., Xie, J. G. & Conney, A. H. Stimulatory effect of topical application of caffeine on UVB-induced apoptosis in the epidermis of p53 and Bax knockout mice. Cancer Res. 64, 5020–5027 (2004).

    Article  CAS  Google Scholar 

  20. Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994).

    Article  CAS  Google Scholar 

  21. Kulms, D. & Schwarz, T. Molecular mechanisms of UV-induced apoptosis. Photodermatol. Photoimmunol. Photomed. 16, 195–201 (2000).

    Article  CAS  Google Scholar 

  22. Rawlings, A. V. & Matts, P. J. Stratum corneum moisturization at the molecular level: an update in relation to the dry skin cycle. J. Invest. Dermatol. 124, 1099–1110 (2005).

    Article  CAS  Google Scholar 

  23. Krysko, D. V. et al. Macrophages use different internalization mechanisms to clear apoptotic and necrotic cells. Cell Death Differ. 13, 2011–2022 (2006).

    Article  CAS  Google Scholar 

  24. Schwarz, A. et al. Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair. Nature Cell Biol. 4, 26–31 (2002).

    Article  CAS  Google Scholar 

  25. Caldelari, R., Suter, M. M., Baumann, D., De Bruin, A. & Muller, E. Long-term culture of murine epidermal keratinocytes. J. Invest. Dermatol. 114, 1064–1065 (2000).

    Article  CAS  Google Scholar 

  26. Presland, R. B., Haydock, P. V., Fleckman, P., Nirunsuksiri, W. & Dale, B. A. Characterization of the human epidermal profilaggrin gene. J. Biol. Chem. 267, 23772–23781 (1992).

    CAS  PubMed  Google Scholar 

  27. Denecker, G. et al. Death receptor-induced apoptotic and necrotic cell death: differential role of caspases and mitochondria. Cell Death Differ. 8, 829–840 (2001).

    Article  CAS  Google Scholar 

  28. Carmeliet, P. et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nature Med. 5, 495–502 (1999).

    Article  CAS  Google Scholar 

  29. Schoonjans, L. et al. Improved generation of germline-competent embryonic stem cell lines from inbred mouse strains. Stem Cells 21, 90–97 (2003).

    Article  Google Scholar 

  30. Chien, A. J., Presland, R. B. & Kuechle, M. K. Processing of native caspase-14 occurs at an atypical cleavage site in normal epidermal differentiation. Biochem. Biophys. Res. Commun. 296, 911–917 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Bredan for editing the manuscript and E. van Damme, A. Meeus and W. Deckers for technical assistance. This work was supported in part by the Interuniversitaire Attractiepolen V, the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, the Epistem 6th framework EC-RTD grant and Ghent University GOA project. G.D. is a postdoctoral fellow at the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, E.H. has an Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie (IWT) predoctoral grant and P.O. had an Emmanuel Verscheuren and an IWT predoctoral grant. R.P. was supported by R01 AR49183 from the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Peter Vandenabeele or Wim Declercq.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures S1, S2, S3, S4 and S5 (PDF 570 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Denecker, G., Hoste, E., Gilbert, B. et al. Caspase-14 protects against epidermal UVB photodamage and water loss. Nat Cell Biol 9, 666–674 (2007). https://doi.org/10.1038/ncb1597

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1597

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing