Cornification Diseases (Skin Cell Death)


The outermost layer of the skin is formed by the cornified envelope (CE), which is the end product of the process of keratinization. This forms a barrier that is essential to protect the internal homeostasis of the organism from the external environment. The process of keratinization proceeds according to a complex and elaborately controlled differentiation program with the coordinated expression of genes encoding specialized components, enzymes, and regulatory molecules. The CE is a specialized structure that replaces the plasma membrane of differentiating keratinocytes and consists of proteins crosslinked by covalent bonds and lipids to form a scaffold. Understanding of the pathologies associated with defects in CE components will help clarify the molecular mechanisms and the physiological endpoints of keratinization. Here, we describe some diseases of keratinization, and give a brief overview on animal models (transgenic and knockout) with defects in the CE formation.

Key concepts:

  • The outermost layer of the skin is formed by the cornified envelope (CE).

  • The CE is a specialized structure that replaces the plasma membrane of differentiating keratinocytes. It consists of proteins crosslinked by covalent bonds and lipids to form a scaffold.

  • The CE is essential to provide the barrier function of the epidermis.

  • The transglutaminase enzymes play a major role in the formation of the CE by catalyzing the formation of crosslinks between specific proteins.

  • Mutations in keratin genes cause a wide variety of epidermal and other epithelial disorders.

  • CE lipids contribute in a significant way to the establishment of barrier function of the epidermis by impermeabilizing the cornified cell and participating in the organization of the intercellular lipid lamellae.

  • Defects in proteases result in barrier function abnormalities or skin diseases.

  • The transcription factor p63 is crucial in epidermis formation, maintaining the progenitorÔÇÉcell populations that are necessary to sustain epithelial development and morphogenesis.

Keywords: apoptosis; cornified envelope; keratinization; cell death; transglutaminase; keratinocyte differentiation; cornification; keratinization

Figure 1.

TG1 enzyme is present in two forms in keratinocytes: as a cytosolic and membrane‐bound enzymes. In proliferating keratinocytes, TG1 is N‐ and S‐myristoylated, while in differentiating keratinocytes it can be N‐myristoylated and S‐palmitoylated. During differentiation, the full‐length enzyme (106 kDa) is also proteolytically processed to form complexes of 10/67/33 kDa (membrane bound) or 67/33, 67, 33 kDa (cytosolic). These different complexes have different specific activities as indicated in the schematic representation. Specific activities are indicated in red as pmol of putrescine/h/pmol of enzyme.

Figure 2.

(a) Assembly pathway for cytoplasmic intermediate filament proteins. The scheme is from monomer to fiber formation. Intermediate filaments are not static structures, merely providing a stable skeleton for cells. A large body of data indicates that they are highly dynamic structures, continually changing their organization and distribution in cells, and exchanging subfilamentous units along their entire length, in response to a variety of extrinsic and intrinsic responses. (b) Mutations in the keratin proteins, which interfere with these dynamic processes between 1A and L1, cause major defects in the cells, resulting in severe pathology (see some example of these indicated in the panel). 1A, 1B, 2A, and 2B are repeat‐containing segments interrupted at three consecutive locations by linker sequences L1, L12, and L2. EBS, epidermolysis bullosa simplex; EH, epidermolytic hyperkeratosis; EPPK, epidermolytic palmoplantar keratoderma; FNEPPK, focal non‐epidermolytic palmoplantar keratoderma; IBS, ichthyosis bullosa of Siemens; MCD, Meesmann's corneal dystrophy; NEPPK, non‐epidermolytic palmoplantar keratoderma; PC, pachyonychia congenita; WSN, white sponge nevus of Cannon.



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Further Reading

Bouwstra JA, Honeywell‐Nguyen PL, Gooris GS et al. (2003) Structure of the skin barrier and its modulation by vesicular formulations. Progress in Lipid Research 42: 1–36.

Denecker G, Ovaere P, Vandenabeele P et al. (2008) Caspase‐14 reveals its secrets. Journal of Cell Biology 180: 451–458.

Ekholm IE, Brattsand M and Egelrud T (2000) Stratum corneum tryptic enzyme in normal epidermis: a missing link in the desquamation process? Journal of Investigative Dermatology 114: 56–63.

Elias PM (2005) Stratum corneum defensive functions: an integrated view. Journal of Investigative Dermatology 125(2): 183–200 Review.

Godsel LM, Hobbs RP and Green KJ (2008) Intermediate filament assembly: dynamics to disease. Trends in Cell Biology 18(1): 28–37.

Kim S and Coulombe PA (2007) Intermediate filament scaffolds fulfill mechanical, organizational, and signaling functions in the cytoplasm. Genes & Development 21(13): 1581–1597.

Madison KC (2003) Barrier function of the skin: ‘la raison d'etre’ of the epidermis. Journal of Investigative Dermatology 121: 231–241.

Watt FM (2002) Role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO Journal 21: 3919–3926.

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Candi, E, McLean, WH, Didona, B, Terrinoni, A, and Melino, G(Dec 2009) Cornification Diseases (Skin Cell Death). In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021986]