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.

The cornified envelope: a model of cell death in the skin

Nature Reviews Molecular Cell Biology volume 6, pages 328–340 (2005)Cite this article

Key Points

  • Keratinocytes exert their functions after cell death to guarantee the stability, mechanical resistance, elasticity, physical-barrier and water-impermeability functions of the skin.

  • These properties are conferred by the cornified envelope where specialized substrates are crosslinked by transglutaminases.

  • Four out of the nine transglutaminases are expressed in the epidermis, where they exert their function in a coordinated way.

  • At least ten distinct proteins function as substrates for epidermal transglutaminases. These proteins end up comprising the cornified envelope of the terminally differentiated corneoytes that make up the cornified layer. The cornified layer has a relative content (% of protein in dry weight) of ∼80% loricrin, 8% small proline-rich proteins (SPRs) and 6% filaggrin.

  • Loricrin and SPRs lack a significant ordered structure, which confers a considerable mobility and flexibility to these molecules. This is crucial for allowing a spring-like elasticity to the epidermis, whereas the intramolecular and intermolecular transglutaminase-crosslinked residues guarantee stability and mechanical resistance.

  • Mutations of transglutaminases and their substrates cause severe skin diseases, such as lamellar ichthyosis.

Abstract

The epidermis functions as a barrier against the environment by means of several layers of terminally differentiated, dead keratinocytes — the cornified layer, which forms the endpoint of epidermal differentiation and death. The cornified envelope replaces the plasma membrane of differentiating keratinocytes and consists of keratins that are enclosed within an insoluble amalgam of proteins, which are crosslinked by transglutaminases and surrounded by a lipid envelope. New insights into the molecular mechanisms and the physiological endpoints of cornification are increasing our understanding of the pathological defects of this unique form of programmed cell death, which is associated with barrier malfunctions and ichthyosis.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Terminal differentiation and apoptosis in the epidermis.
Figure 2: Progressive steps in the formation of the cornified envelope.
Figure 3: Lack of ordered structure in the substrates of skin transglutaminases.

References

  1. Steven, A. C. & Steinert, P. M. Protein composition of cornified cell envelopes of epidermal keratinocytes. J. Cell Sci. 107, 693–700 (1994).

    CAS  PubMed  Google Scholar 

  2. Steinert, P. M. & Marekov, L. N. The proteins elafin, filaggrin, keratin intermediate filaments, loricrin, and small proline-rich proteins 1 and 2 are isodipeptide cross-linked components of the human epidermal cornified cell envelope. J. Biol. Chem. 270, 17702–17711 (1995).

    CAS  PubMed  Google Scholar 

  3. Kalinin, A., Marekov, L. N. & Steinert, P. M. Assembly of the epidermal cornified cell envelope. J. Cell Sci. 114, 3069–3070 (2001).

    CAS  PubMed  Google Scholar 

  4. Reichert, U., Michel, S. & Schmidt, R. The Cornified Envelope: A Key Structure of Terminally Differentiating Keratinocytes. (eds Darmon, M. & Blumenberg, M.) (Academic Press, London, 1993).

    Google Scholar 

  5. Michel, S., Schmidt, R., Shroot, B. & Reichert, U. Morphological and biochemical characterization of the cornified envelopes from human epidermal keratinocytes of different origin. J. Invest. Dermatol. 91, 11–15 (1988).

    CAS  PubMed  Google Scholar 

  6. Kalinin, A. E., Kajava, A. V. & Steinert, P. M. Epithelial barrier function: assembly and structural features of the cornified cell envelope. Bioessays 24, 789–800 (2002).

    CAS  PubMed  Google Scholar 

  7. Fuchs, E. & Cleveland, D. W. A structural scaffolding of intermediate filaments in health and disease. Science 279, 514–519 (1998).

    CAS  PubMed  Google Scholar 

  8. Strelkov, S. V., Herrmann, H. & Aebi, U. Molecular architecture of intermediate filaments. Bioessays 25, 243–251 (2003).

    CAS  PubMed  Google Scholar 

  9. Porter, R. M. & Lane, E. B. Phenotypes, genotypes and their contribution to understanding keratin function. Trends Genet. 19, 278–285 (2003).

    CAS  PubMed  Google Scholar 

  10. Serre, G. et al. Identification of late differentiation antigens of human cornified epithelia, expressed in re-organized desmosomes and bound to cross-linked envelope. J. Invest. Dermatol. 97, 1061–1072 (1991).

    CAS  PubMed  Google Scholar 

  11. Steinert, P. M., Kartasova, T. & Marekov, L. N. Biochemical evidence that small proline-rich proteins and trichohyalin function in epithelia by modulation of the biomechanical properties of their cornified cell envelopes. J. Biol. Chem. 273, 11758–11769 (1998).

    CAS  PubMed  Google Scholar 

  12. Kartasova, T. et al. Sequence and expression patterns of mouse SPR1: correlation of expression with epithelial function. J. Invest. Dermatol. 106, 294–304 (1996).

    CAS  PubMed  Google Scholar 

  13. Lorand, L. & Graham, R. M. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nature Rev. Mol. Cell Biol. 4, 140–156 (2003).

    CAS  Google Scholar 

  14. Koch, P. J. et al. Lessons from loricrin-deficient mice: compensatory mechanisms maintaining skin barrier function in the absence of a major cornified envelope protein. J. Cell Biol. 151, 389–400 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Djian, P., Easley, K. & Green, H. Targeted ablation of the murine involucrin gene. J. Cell Biol. 151, 381–388 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Candi, E. et al. A highly conserved lysine residue on the head domain of type II keratins is essential for the attachment of keratin intermediate filaments to the cornified cell envelope through isopeptide crosslinking by transglutaminases. Proc. Natl Acad. Sci. USA 95, 2067–2072 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kimonis, V. et al. A mutation in the V1 end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma. J. Invest. Dermatol. 103, 764–769 (1994).

    CAS  PubMed  Google Scholar 

  19. Roop, D. R., Krieg, T. M., Mehrel, T., Cheng, C. K. & Yuspa, S. H. Transcriptional control of high molecular weight keratin gene expression in multistage mouse skin carcinogenesis. Cancer Res. 48, 3245–3252 (1988).

    CAS  PubMed  Google Scholar 

  20. Broome, A. M., Ryan, D. & Eckert, R. L. S100 protein subcellular localization during epidermal differentiation and psoriasis. J. Histochem. Cytochem. 51, 675–685 (2003).

    CAS  PubMed  Google Scholar 

  21. Ruse, M. et al. S100A7, S100A10, and S100A11 are transglutaminase substrates. Biochemistry 40, 3167–3173 (2001).

    CAS  PubMed  Google Scholar 

  22. Ruse, M., Broome, A. M. & Eckert, R. L. S100A7 (psoriasin) interacts with epidermal fatty acid binding protein and localizes in focal adhesion-like structures in cultured keratinocytes. J. Invest. Dermatol. 121, 132–141 (2003).

    CAS  PubMed  Google Scholar 

  23. Mischke, D., Korge, B. P., Marenholz, I., Volz, A. & Ziegler, A. Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex ('epidermal differentiation complex') on human chromosome 1q21. J. Invest. Dermatol. 106, 989–992 (1996).

    CAS  PubMed  Google Scholar 

  24. O'Keefe, E. J., Hamilton, E. H., Lee, S. C. & Steinert, P. Trichohyalin: a structural protein of hair, tongue, nail, and epidermis. J. Invest. Dermatol. 101, 65S–71S (1993).

    CAS  PubMed  Google Scholar 

  25. Marshall, D., Hardman, M. J., Nield, K. M. & Byrne, C. Differentially expressed late constituents of the epidermal cornified envelope. Proc. Natl Acad. Sci. USA 98, 13031–13036 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Rice, R. H. & Green, H. The cornified envelope of terminally differentiated human epidermal keratinocytes consists of cross-linked protein. Cell 11, 417–422 (1977).

    CAS  PubMed  Google Scholar 

  27. Eckert, R. L. & Green, H. Structure and evolution of the human involucrin gene. Cell 46, 583–589 (1986).

    CAS  PubMed  Google Scholar 

  28. Yaffe, M. B., Beegen, H. & Eckert, R. L. Biophysical characterization of involucrin reveals a molecule ideally suited to function as an intermolecular cross-bridge of the keratinocyte cornified envelope. J. Biol. Chem. 267, 12233–12238 (1992).

    CAS  PubMed  Google Scholar 

  29. Simon, M. & Green, H. The glutamine residues reactive in transglutaminase-catalyzed cross-linking of involucrin. J. Biol. Chem. 263, 18093–18098 (1988).

    CAS  PubMed  Google Scholar 

  30. Nemes, Z., Marekov, L. N., Fesus, L. & Steinert, P. M. A novel function for transglutaminase 1: attachment of long-chain ω-hydroxyceramides to involucrin by ester bond formation. Proc. Natl Acad. Sci. USA 96, 8402–8407 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hohl, D. et al. Characterization of human loricrin. Structure and function of a new class of epidermal cell envelope proteins. J. Biol. Chem. 266, 6626–6636 (1991).

    CAS  PubMed  Google Scholar 

  32. Steinert, P. M. et al. Glycine loops in proteins: their occurrence in certain intermediate filament chains, loricrins and single-stranded RNA binding proteins. Int. J. Biol. Macromol. 13, 130–139 (1991).

    CAS  PubMed  Google Scholar 

  33. Robinson, N. A., Lapic, S., Welter, J. F. & Eckert, R. L. S100A11, S100A10, annexin I, desmosomal proteins, small proline-rich proteins, plasminogen activator inhibitor-2, and involucrin are components of the cornified envelope of cultured human epidermal keratinocytes. J. Biol. Chem. 272, 12035–12046 (1997).

    CAS  PubMed  Google Scholar 

  34. Steinert, P. M. Structure, function, and dynamics of keratin intermediate filaments. J. Invest. Dermatol. 100, 729–734 (1993).

    CAS  PubMed  Google Scholar 

  35. Candi, E. et al. Biochemical, structural, and transglutaminase substrate properties of human loricrin, the major epidermal cornified cell envelope protein. J. Biol. Chem. 270, 26382–26390 (1995).

    CAS  PubMed  Google Scholar 

  36. Yoneda, K. & Steinert, P. M. Overexpression of human loricrin in transgenic mice produces a normal phenotype. Proc. Natl Acad. Sci. USA 90, 10754–10758 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Steven, A. C., Bisher, M. E., Roop, D. R. & Steinert, P. M. Biosynthetic pathways of filaggrin and loricrin — two major proteins expressed by terminally differentiated epidermal keratinocytes. J. Struct. Biol. 104, 150–162 (1990).

    CAS  PubMed  Google Scholar 

  38. Takahashi, M., Tezuka, T. & Katunuma, N. Phosphorylated cystatin α is a natural substrate of epidermal transglutaminase for formation of skin cornified envelope. FEBS Lett. 308, 79–82 (1992).

    CAS  PubMed  Google Scholar 

  39. Candi, E. et al. Transglutaminase cross-linking properties of the small proline-rich 1 family of cornified cell envelope proteins. Integration with loricrin. J. Biol. Chem. 274, 7226–7237 (1999).

    CAS  PubMed  Google Scholar 

  40. Tarcsa, E. et al. Structural and transglutaminase substrate properties of the small proline-rich 2 family of cornified cell envelope proteins. J. Biol. Chem. 273, 23297–23303 (1998).

    CAS  PubMed  Google Scholar 

  41. Steinert, P. M. et al. Transglutaminase crosslinking and structural studies of the human small proline rich 3 protein. Cell Death Differ. 6, 916–930 (1999).

    CAS  PubMed  Google Scholar 

  42. Jarnik, M., Kartasova, T., Steinert, P. M., Lichti, U. & Steven, A. C. Differential expression and cell envelope incorporation of small proline-rich protein 1 in different cornified epithelia. J. Cell Sci. 109, 1381–1391 (1996).

    CAS  PubMed  Google Scholar 

  43. Steinert, P. M., Candi, E., Kartasova, T. & Marekov, L. Small proline-rich proteins are cross-bridging proteins in the cornified cell envelopes of stratified squamous epithelia. J. Struct. Biol. 122, 76–85 (1998).

    CAS  PubMed  Google Scholar 

  44. McKinley-Grant, L. J. et al. Characterization of a cDNA clone encoding human filaggrin and localization of the gene to chromosome region 1q21. Proc. Natl Acad. Sci. USA 86, 4848–4852 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Gan, S. Q., McBride, O. W., Idler, W. W., Markova, N. & Steinert, P. M. Organization, structure, and polymorphisms of the human profilaggrin gene. Biochemistry 29, 9432–9440 (1990).

    CAS  PubMed  Google Scholar 

  46. Resing, K. A., Dale, B. A. & Walsh, K. A. Multiple copies of phosphorylated filaggrin in epidermal profilaggrin demonstrated by analysis of tryptic peptides. Biochemistry 24, 4167–4175 (1985).

    CAS  PubMed  Google Scholar 

  47. Resing, K. A., Johnson, R. S. & Walsh, K. A. Characterization of protease processing sites during conversion of rat profilaggrin to filaggrin. Biochemistry 32, 10036–10045 (1993).

    CAS  PubMed  Google Scholar 

  48. Steinert, P. M., Cantieri, J. S., Teller, D. C., Lonsdale-Eccles, J. D. & Dale, B. A. Characterization of a class of cationic proteins that specifically interact with intermediate filaments. Proc. Natl Acad. Sci. USA 78, 4097–4101 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Mack, J. W., Steven, A. C. & Steinert, P. M. The mechanism of interaction of filaggrin with intermediate filaments. The ionic zipper hypothesis. J. Mol. Biol. 232, 50–66 (1993).

    CAS  PubMed  Google Scholar 

  50. Markova, N. G. et al. Profilaggrin is a major epidermal calcium-binding protein. Mol. Cell Biol. 13, 613–625 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Watt, F. M. Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J. 21, 3919–3926 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Simon, M. et al. Refined characterization of corneodesmosin proteolysis during terminal differentiation of human epidermis and its relationship to desquamation. J. Biol. Chem. 276, 20292–20299 (2001).

    CAS  PubMed  Google Scholar 

  53. Brattsand, M. & Egelrud, T. Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquamation. J. Biol. Chem. 274, 30033–30040 (1999).

    CAS  PubMed  Google Scholar 

  54. Ekholm, I. E., Brattsand, M. & Egelrud, T. Stratum corneum tryptic enzyme in normal epidermis: a missing link in the desquamation process? J. Invest. Dermatol. 114, 56–63 (2000).

    CAS  PubMed  Google Scholar 

  55. Simon, M., Montezin, M., Guerrin, M., Durieux, J. J. & Serre, G. Characterization and purification of human corneodesmosin, an epidermal basic glycoprotein associated with corneocyte-specific modified desmosomes. J. Biol. Chem. 272, 31770–31776 (1997).

    CAS  PubMed  Google Scholar 

  56. Guerrin, M. et al. Expression cloning of human corneodesmosin proves its identity with the product of the S gene and allows improved characterization of its processing during keratinocyte differentiation. J. Biol. Chem. 273, 22640–22647 (1998).

    CAS  PubMed  Google Scholar 

  57. Amagai, M. Autoimmunity against desmosomal cadherins in pemphigus. J. Dermatol. Sci. 20, 92–102 (1999).

    CAS  PubMed  Google Scholar 

  58. Armstrong, D. K. et al. Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum. Mol. Genet. 8, 143–148 (1999).

    CAS  PubMed  Google Scholar 

  59. McGrath, J. A. et al. Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome. Nature Genet. 17, 240–244 (1997).

    CAS  PubMed  Google Scholar 

  60. Sakuntabhai, A. et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nature Genet. 21, 271–277 (1999).

    CAS  PubMed  Google Scholar 

  61. Hu, Z. et al. Mutations in ATP2C1, encoding a calcium pump, cause Hailey–Hailey disease. Nature Genet. 24, 61–65 (2000).

    CAS  PubMed  Google Scholar 

  62. Kim, S. Y. & Bae, C. D. Calpain inhibitors reduce the cornified cell envelope formation by inhibiting proteolytic processing of transglutaminase 1. Exp. Mol. Med. 30, 257–262 (1998).

    CAS  PubMed  Google Scholar 

  63. Kim, I. G. et al. Structure and organization of the human transglutaminase 3 gene: evolutionary relationship to the transglutaminase family. J. Invest. Dermatol. 103, 137–142 (1994).

    CAS  PubMed  Google Scholar 

  64. Egberts, F. et al. Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation. J. Cell Sci. 117, 2295–2307 (2004).

    CAS  PubMed  Google Scholar 

  65. Candi, E. et al. Transglutaminase 1 mutations in lamellar ichthyosis. Loss of activity due to failure of activation by proteolytic processing. J. Biol. Chem. 273, 13693–13702 (1998).

    CAS  PubMed  Google Scholar 

  66. List, K. et al. Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1. J. Cell Biol. 163, 901–910 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Schwarz, G. et al. Cathepsin S activity is detectable in human keratinocytes and is selectively upregulated upon stimulation with interferon-γ. J. Invest. Dermatol. 119, 44–49 (2002).

    CAS  PubMed  Google Scholar 

  68. Bernard, D. et al. Analysis of proteins with caseinolytic activity in a human stratum corneum extract revealed a yet unidentified cysteine protease and identified the so-called 'stratum corneum thiol protease' as cathepsin l2. J. Invest. Dermatol. 120, 592–600 (2003).

    CAS  PubMed  Google Scholar 

  69. Benavides, F. et al. Impaired hair follicle morphogenesis and cycling with abnormal epidermal differentiation in nackt mice, a cathepsin L-deficient mutation. Am. J. Pathol. 161, 693–703 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Roth, W. et al. Cathepsin L deficiency as molecular defect of furless: hyperproliferation of keratinocytes and pertubation of hair follicle cycling. FASEB J. 14, 2075–2086 (2000).

    CAS  PubMed  Google Scholar 

  71. Miyachi, Y. et al. Biochemical demonstration and immunohistochemical localization of calpain in human skin. J. Invest. Dermatol. 86, 346–349 (1986).

    CAS  PubMed  Google Scholar 

  72. Yamazaki, M. et al. Cytoplasmic processing of human profilaggrin by active mu-calpain. Biochem. Biophys. Res. Commun. 235, 652–656 (1997).

    CAS  PubMed  Google Scholar 

  73. Zimmerman, U. J., Boring, L., Pak, J. H., Mukerjee, N. & Wang, K. K. The calpain small subunit gene is essential: its inactivation results in embryonic lethality. IUBMB Life 50, 63–68 (2000).

    CAS  PubMed  Google Scholar 

  74. 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).

    CAS  PubMed  Google Scholar 

  75. Hansson, L. et al. Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase. J. Biol. Chem. 269, 19420–19426 (1994).

    CAS  PubMed  Google Scholar 

  76. Sondell, B., Thornell, L. E. & Egelrud, T. Evidence that stratum corneum chymotryptic enzyme is transported to the stratum corneum extracellular space via lamellar bodies. J. Invest. Dermatol. 104, 819–823 (1995).

    CAS  PubMed  Google Scholar 

  77. Yang, T. et al. Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5−/− mice. Genes Dev. 18, 2354–2358 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Bouwstra, J. A., Honeywell-Nguyen, P. L., Gooris, G. S. & Ponec, M. Structure of the skin barrier and its modulation by vesicular formulations. Prog. Lipid Res. 42, 1–36 (2003).

    CAS  PubMed  Google Scholar 

  79. Madison, K. C. Barrier function of the skin: 'la raison d'etre' of the epidermis. J. Invest. Dermatol. 121, 231–241 (2003).

    CAS  PubMed  Google Scholar 

  80. Freinkel, R. K. & Traczyk, T. N. Lipid composition and acid hydrolase content of lamellar granules of fetal rat epidermis. J. Invest. Dermatol. 85, 295–298 (1985).

    CAS  PubMed  Google Scholar 

  81. Landmann, L. The epidermal permeability barrier. Anat. Embryol. (Berl) 178, 1–13 (1988).

    CAS  Google Scholar 

  82. Grayson, S. et al. Lamellar body-enriched fractions from neonatal mice: preparative techniques and partial characterization. J. Invest. Dermatol. 85, 289–294 (1985).

    CAS  PubMed  Google Scholar 

  83. Menon, G. K., Feingold, K. R. & Elias, P. M. Lamellar body secretory response to barrier disruption. J. Invest. Dermatol. 98, 279–289 (1992).

    CAS  PubMed  Google Scholar 

  84. Holleran, W. M. et al. Consequences of β-glucocerebrosidase deficiency in epidermis. Ultrastructure and permeability barrier alterations in Gaucher disease. J. Clin. Invest. 93, 1756–1764 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Jensen, J. M., Schutze, S., Forl, M., Kronke, M. & Proksch, E. Roles for tumor necrosis factor receptor p55 and sphingomyelinase in repairing the cutaneous permeability barrier. J. Clin. Invest. 104, 1761–1770 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Schmuth, M. et al. Permeability barrier disorder in Niemann–Pick disease: sphingomyelin-ceramide processing required for normal barrier homeostasis. J. Invest. Dermatol. 115, 459–466 (2000).

    CAS  PubMed  Google Scholar 

  87. Attar, P. S. et al. Inhibition of retinoid signaling in transgenic mice alters lipid processing and disrupts epidermal barrier function. Mol. Endocrinol. 11, 792–800 (1997).

    CAS  PubMed  Google Scholar 

  88. Herrmann, T. et al. Mice with targeted disruption of the fatty acid transport protein 4 (Fatp 4, Slc27a4) gene show features of lethal restrictive dermopathy. J. Cell Biol. 161, 1105–1115 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Stone, S. J. et al. Lipopenia and skin barrier abnormalities in DGAT2-deficient mice. J. Biol. Chem. 279, 11767–11776 (2004).

    CAS  PubMed  Google Scholar 

  90. Westerberg, R. et al. Role for ELOVL3 and fatty acid chain length in development of hair and skin function. J. Biol. Chem. 279, 5621–5629 (2004).

    CAS  PubMed  Google Scholar 

  91. Elias, P. M. & Friend, D. S. The permeability barrier in mammalian epidermis. J. Cell Biol. 65, 180–191 (1975).

    CAS  PubMed  Google Scholar 

  92. Elias, P. M., Goerke, J. & Friend, D. S. Mammalian epidermal barrier layer lipids: composition and influence on structure. J. Invest. Dermatol. 69, 535–546 (1977).

    CAS  PubMed  Google Scholar 

  93. Forslind, B. A domain mosaic model of the skin barrier. Acta Derm. Venereol. 74, 1–6 (1994).

    CAS  PubMed  Google Scholar 

  94. Norlen, L. Skin barrier formation: the membrane folding model. J. Invest. Dermatol. 117, 823–829 (2001).

    CAS  PubMed  Google Scholar 

  95. Goldstein, A. M. & Abramovits, W. Ceramides and the stratum corneum: structure, function, and new methods to promote repair. Int. J. Dermatol. 42, 256–259 (2003).

    CAS  PubMed  Google Scholar 

  96. Ponec, M., Weerheim, A., Lankhorst, P. & Wertz, P. New acylceramide in native and reconstructed epidermis. J. Invest. Dermatol. 120, 581–588 (2003).

    CAS  PubMed  Google Scholar 

  97. Marekov, L. N. & Steinert, P. M. Ceramides are bound to structural proteins of the human foreskin epidermal cornified cell envelope. J. Biol. Chem. 273, 17763–17770 (1998).

    CAS  PubMed  Google Scholar 

  98. Huber, M. et al. Mutations of keratinocyte transglutaminase in lamellar ichthyosis. Science 267, 525–528 (1995).

    CAS  PubMed  Google Scholar 

  99. Russell, L. J. et al. Mutations in the gene for transglutaminase 1 in autosomal recessive lamellar ichthyosis. Nature Genet. 9, 279–283 (1995).

    CAS  PubMed  Google Scholar 

  100. Fischer, J. et al. Two new loci for autosomal recessive ichthyosis on chromosomes 3p21 and 19p12-q12 and evidence for further genetic heterogeneity. Am. J. Hum. Genet. 66, 904–913 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Krebsova, A. et al. Identification, by homozygosity mapping, of a novel locus for autosomal recessive congenital ichthyosis on chromosome 17p, and evidence for further genetic heterogeneity. Am. J. Hum. Genet. 69, 216–222 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Lefevre, C. et al. Mutations in the transporter ABCA12 are associated with lamellar ichthyosis type 2. Hum. Mol. Genet. 12, 2369–2378 (2003).

    CAS  PubMed  Google Scholar 

  103. Parmentier, L. et al. Mapping of a second locus for lamellar ichthyosis to chromosome 2q33-35. Hum. Mol. Genet. 5, 555–559 (1996).

    CAS  PubMed  Google Scholar 

  104. Maestrini, E. et al. A molecular defect in loricrin, the major component of the cornified cell envelope, underlies Vohwinkel's syndrome. Nature Genet. 13, 70–77 (1996).

    CAS  PubMed  Google Scholar 

  105. Ishida-Yamamoto, A. et al. The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the cornified cell envelope. Am. J. Hum. Genet. 61, 581–589 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Jarnik, M. et al. Quasi-normal cornified cell envelopes in loricrin knockout mice imply the existence of a loricrin backup system. J. Invest. Dermatol. 118, 102–109 (2002).

    CAS  PubMed  Google Scholar 

  107. Suga, Y. et al. Transgenic mice expressing a mutant form of loricrin reveal the molecular basis of the skin diseases, Vohwinkel syndrome and progressive symmetric erythrokeratoderma. J. Cell Biol. 151, 401–412 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Steinert, P. M. & Parry, D. A. Intermediate filaments: conformity and diversity of expression and structure. Annu. Rev. Cell Biol. 1, 41–65 (1985).

    CAS  PubMed  Google Scholar 

  109. Steinert, P. M. & Roop, D. R. Molecular and cellular biology of intermediate filaments. Annu. Rev. Biochem. 57, 593–625 (1988).

    CAS  PubMed  Google Scholar 

  110. Steinert, P. M. & Liem, R. K. Intermediate filament dynamics. Cell 60, 521–523 (1990).

    CAS  PubMed  Google Scholar 

  111. Shapiro, L. J. et al. Enzymatic basis of typical X-linked icthyosis. Lancet 2, 756–757 (1978).

    CAS  PubMed  Google Scholar 

  112. Nemes, Z., Demeny, M., Marekov, L. N., Fesus, L. & Steinert, P. M. Cholesterol 3-sulfate interferes with cornified envelope assembly by diverting transglutaminase 1 activity from the formation of cross-links and esters to the hydrolysis of glutamine. J. Biol. Chem. 275, 2636–2646 (2000).

    CAS  PubMed  Google Scholar 

  113. Jobard, F. et al. Lipoxygenase-3 (ALOXE3) and 12(R)-lipoxygenase (ALOX12B) are mutated in non-bullous congenital ichthyosiform erythroderma (NCIE) linked to chromosome 17p13. 1. Hum. Mol. Genet. 11, 107–113 (2002).

    CAS  PubMed  Google Scholar 

  114. De Laurenzi, V. et al. Sjogren–Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nature Genet. 12, 52–57 (1996).

    CAS  PubMed  Google Scholar 

  115. Sidransky, E., Sherer, D. M. & Ginns, E. I. Gaucher disease in the neonate: a distinct Gaucher phenotype is analogous to a mouse model created by targeted disruption of the glucocerebrosidase gene. Pediatr. Res. 32, 494–498 (1992).

    CAS  PubMed  Google Scholar 

  116. Lefevre, C. et al. Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin–Dorfman syndrome. Am. J. Hum. Genet. 69, 1002–1012 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Akiyama, M., Sawamura, D., Nomura, Y., Sugawara, M. & Shimizu, H. Truncation of CGI-58 protein causes malformation of lamellar granules resulting in ichthyosis in Dorfman–Chanarin syndrome. J. Invest. Dermatol. 121, 1029–1034 (2003).

    CAS  PubMed  Google Scholar 

  118. Chavanas, S. et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nature Genet. 25, 141–142 (2000).

    CAS  PubMed  Google Scholar 

  119. Hart, T. C. et al. Mutations of the cathepsin C gene are responsible for Papillon–Lefevre syndrome. J. Med. Genet. 36, 881–887 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Steinert, P. M., Chung, S. I. & Kim, S. Y. Inactive zymogen and highly active proteolytically processed membrane-bound forms of the transglutaminase 1 enzyme in human epidermal keratinocytes. Biochem. Biophys. Res. Commun. 221, 101–106 (1996).

    CAS  PubMed  Google Scholar 

  121. Steinert, P. M., Kim, S. Y., Chung, S. I. & Marekov, L. N. The transglutaminase 1 enzyme is variably acylated by myristate and palmitate during differentiation in epidermal keratinocytes. J. Biol. Chem. 271, 26242–26250 (1996).

    CAS  PubMed  Google Scholar 

  122. Kim, S. Y., Chung, S. I. & Steinert, P. M. Highly active soluble processed forms of the transglutaminase 1 enzyme in epidermal keratinocytes. J. Biol. Chem. 270, 18026–18035 (1995).

    CAS  PubMed  Google Scholar 

  123. Piacentini, M. et al. The expression of 'tissue' transglutaminase in two human cancer cell lines is related with the programmed cell death (apoptosis). Eur. J. Cell Biol. 54, 246–254 (1991).

    CAS  PubMed  Google Scholar 

  124. Melino, G. et al. Tissue transglutaminase and apoptosis: sense and antisense transfection studies with human neuroblastoma cells. Mol. Cell Biol. 14, 6584–6596 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. De Laurenzi, V. & Melino, G. Gene disruption of tissue transglutaminase. Mol. Cell. Biol. 21, 148–155 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Boehm, J. E., Singh, U., Combs, C., Antonyak, M. A. & Cerione, R. A. Tissue transglutaminase protects against apoptosis by modifying the tumor suppressor protein p110 Rb. J. Biol. Chem. 277, 20127–20130 (2002).

    CAS  PubMed  Google Scholar 

  127. Tarcsa, E. et al. The fate of trichohyalin. Sequential post-translational modifications by peptidyl-arginine deiminase and transglutaminases. J. Biol. Chem. 272, 27893–27901 (1997).

    CAS  PubMed  Google Scholar 

  128. Candi, E. et al. Expression of transglutaminase 5 in normal and pathologic human epidermis. J. Invest. Dermatol. 119, 670–677 (2002).

    CAS  PubMed  Google Scholar 

  129. Candi, E. et al. Transglutaminase 5 cross-links loricrin, involucrin, and small proline-rich proteins in vitro. J. Biol. Chem. 276, 35014–35023 (2001).

    CAS  PubMed  Google Scholar 

  130. Shirai, H., Blundell, T. L. & Mizuguchi, K. A novel superfamily of enzymes that catalyze the modification of guanidino groups. Trends Biochem. Sci. 26, 465–468 (2001).

    CAS  PubMed  Google Scholar 

  131. Ishida-Yamamoto, A. et al. Decreased deiminated keratin K1 in psoriatic hyperproliferative epidermis. J. Invest. Dermatol. 114, 701–705 (2000).

    CAS  PubMed  Google Scholar 

  132. Ishigami, A. et al. Human peptidylarginine deiminase type II: molecular cloning, gene organization, and expression in human skin. Arch Biochem. Biophys. 407, 25–31 (2002).

    CAS  PubMed  Google Scholar 

  133. Senshu, T., Akiyama, K. & Nomura, K. Identification of citrulline residues in the V subdomains of keratin K1 derived from the cornified layer of newborn mouse epidermis. Exp. Dermatol. 8, 392–401 (1999).

    CAS  PubMed  Google Scholar 

  134. Ishida-Yamamoto, A. et al. Sequential reorganization of cornified cell keratin filaments involving filaggrin-mediated compaction and keratin 1 deimination. J. Invest. Dermatol. 118, 282–287 (2002).

    CAS  PubMed  Google Scholar 

  135. Tsuji, Y., Akiyama, M., Arita, K., Senshu, T. & Shimizu, H. Changing pattern of deiminated proteins in developing human epidermis. J. Invest. Dermatol. 120, 817–822 (2003).

    CAS  PubMed  Google Scholar 

  136. Tarcsa, E. et al. Protein unfolding by peptidylarginine deiminase. Substrate specificity and structural relationships of the natural substrates trichohyalin and filaggrin. J. Biol. Chem. 271, 30709–30716 (1996).

    CAS  PubMed  Google Scholar 

  137. Jansen, G. A. et al. Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nature Genet. 17, 190–193 (1997).

    CAS  PubMed  Google Scholar 

  138. van den Brink, D. M. et al. Identification of PEX7 as the second gene involved in Refsum disease. Am. J. Hum. Genet. 72, 471–477 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Braverman, N. et al. Mutations in the gene encoding 3β-hydroxysteroid-δ8, δ7-isomerase cause X-linked dominant Conradi–Hunermann syndrome. Nature Genet. 22, 291–294 (1999).

    CAS  PubMed  Google Scholar 

  140. Grange, D. K., Kratz, L. E., Braverman, N. E. & Kelley, R. I. CHILD syndrome caused by deficiency of 3β-hydroxysteroid-δ8, δ7-isomerase. Am. J. Med. Genet. 90, 328–335 (2000).

    CAS  PubMed  Google Scholar 

  141. Konig, A., Happle, R., Bornholdt, D., Engel, H. & Grzeschik, K. H. Mutations in the NSDHL gene, encoding a 3β-hydroxysteroid dehydrogenase, cause CHILD syndrome. Am. J. Med. Genet. 90, 339–346 (2000).

    CAS  PubMed  Google Scholar 

  142. Waterham, H. R. & Wanders, R. J. Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith–Lemli–Opitz syndrome. Biochim. Biophys. Acta 1529, 340–356 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to dedicate this manuscript to Peter M. Steinert, whose sudden and premature loss deprived us all of a great master and teacher. The first draft of this manuscript was written by Peter and, as pupils and friends of his, we would like to express our deepest appreciation for his teaching. We would also like to thank D. Bernard, A. Terrinoni and R. A. Knight for helpful discussions and criticism. Some of the work from which this review originated was supported by grants from the National Institutes of Health to P. M. Steinert, L'Oreal to R.S., Telethon to E.C., and by grants from the Medical Research Council, AIRC (Associazione Italiana Ricerca contro il Cancro), Telethon, the European Union, MIUR (Ministero dell'Istruzione, dell'Università e della Ricerca) and MinSan to G.M.

Author information

Authors and Affiliations

  1. c/o Department of Experimental Medicine, Biochemistry Laboratory, IDI-IRCCS, University of Rome Tor Vergata, Rome, 00133, Italy

    Eleonora Candi & Gerry Melino

  2. L'Orèal, Life Sciences Research, Clichy, France

    Rainer Schmidt

  3. Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Lancaster Road, PO Box 138, Leicester, LE1 9HN, UK

    Gerry Melino

Authors
  1. Eleonora Candi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rainer Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gerry Melino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerry Melino.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez

ABCA12

ALOXE3

ALOX12B

Spink5

OMIM

Chanarin–Dorfman syndrome

Gaucher disease

lamellar ichthyosis

Netherton syndrome

nonbullous congenital ichthyosiform erythroderma

progressive symmetric erythrokeratodermia

Sjögren–Larsson syndrome

Vohwinkel syndrome

X-linked ichthyosis

Swiss-Prot

μ-calpain (I)

cathepsin D

corneodesmosin

desmoglein-1

desmocollin-1

elafin

envoplakin

furin

involucrin

K1

K2e

K5

K9

K10

K14

loricrin

m-calpain (II)

periplakin

plakophilin-1

profilaggrin

S100A7

S100A10

S100A11

TG1

TG2

TG3

TG5

trichohyalin

FURTHER INFORMATION

The Human Intermediate Filament Mutation Database

Glossary

CORNIFICATION

The process of terminal keratinocyte differentiation, also known as keratinization or cornified-envelope formation, which allows the formation of the epidermal barrier (cornified layer) in the skin.

EPIDERMIS

The external, uppermost multilayered compartment of the skin, which has evolved in mammals to provide a physical and permeability barrier for the organism. It is separated by a basal lamina from the underlying dermis.

CORNIFIED ENVELOPE

An insoluble protein structure that is assembled by TGs to replace the plasma membrane in corneocytes where it functions as a scaffold for lipid attachment. Corneocytes reside in the uppermost layer of the skin and constitute a barrier for the organism against the external environment.

CORNIFIED LAYER

The uppermost layer of the epidermis, previously known as the stratum corneum. It is formed by flattened dead-cell remnants to create a physical barrier for the skin.

DESQUAMATION

The physiological process of shedding dead corneocytes from the uppermost layer of the epidermis. Desquamation counterbalances regeneration to maintain epidermal homeostasis.

KERATIN INTERMEDIATE FILAMENT

(KIF). A keratin structure that forms the cytoskeleton of all cells. KIFs are grouped into six types: I (acidic keratins), II (neutral–basic keratins); III (desmin, vimentin, peripherin and glial filament proteins); IV (neurofilaments including α-internexin); V (nuclear lamins); and VI (nestin).

DESMOSOME

A structure that contains integrins and connects the keratin-filament cytoskeletons of adjacent cells, and through which the basal layer adheres to the basal lamina. During terminal keratinocyte differentiation, TGs crosslink specific proteins onto desmosomes, forming corneodesmosomes.

NUCLEAR LAMINA

A nuclear-membrane-associated protein structure that is made up of type-V KIFs.

CORNEOCYTE

A terminally differentiated keratinocyte that resides in the cornified layer (or stratum corneum). Corneocytes are dead, but still carry out functions such as forming the mechanical and water barrier that protects the skin.

TRANSGLUTAMINASE

(TG). A Ca2+-dependent enzyme that catalyses the formation of Nε-(γ-glutamyl)lysine bonds between proteins. Three different TGs are involved in the formation of the cornified envelope in the skin.

CORNEODESMOSOME

An adhesive structure within the cornified layer that resides between corneocytes and is generated by modifications (TGs that crosslink desmoglein-1, desmocollin-1, corneodesmin) of desmosomes during terminal keratinocyte differentiation.

EF HAND

A protein motif that can bind Ca2+.

FOCAL ADHESION

A cell-to-substrate adhesion structure that anchors the ends of actin microfilaments (stress fibres) and mediates strong attachment to substrates.

HEMIDESMOSOME

A specialized junction between epithelial cells and the extracellular matrix that is mediated by integrins and is associated with KIFs.

ADHERENS JUNCTION

An actin-filament-associated, epithelial cell–cell junction that has classic cadherins as its core component.

XEROSIS

Abnormal dryness, especially of the skin or the eye.

ICHTHYOSIS

A dermatological disorder in which the keratinocyte cornified envelope is abnormal, which results in a defective external layer (cornified layer). From the greek Ichthyos, which means fish, to indicate the scaly skin like that of a fish.

ALOPECIA

The loss of hair.

LAMELLAR BODY

A small multilayer cytosolic organelle that is surrounded by a membrane.

HYPERKERATOSIS

Thickening of the skin caused by an increased thickness of the cornified layer.

ERYTHRODERMA

Reddening of the skin due to inflammatory skin disease. It often precedes or is associated with exfoliation (skin peeling off in scales or layers) when it might also be known as exfoliative dermatitis.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Candi, E., Schmidt, R. & Melino, G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol 6, 328–340 (2005). https://doi.org/10.1038/nrm1619

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm1619

This article is cited by

Search

Advanced 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