Cornification of the Skin: A Non‐apoptotic Cell Death Mechanism


The most important function of the epidermis is to form a barrier against the environment by means of several layers of terminally differentiated, dead keratinocytes, the cornified envelope (CE). CEs consist of keratins enclosed within an insoluble amalgam of proteins and lipids. Transglutaminase enzymes catalyse the formation of characteristic crosslinks between structural proteins to form the protein part of the CE. Another form of cell death, that is, apoptosis, which has a completely different molecular mechanism and physiological significance, also occurs in the skin. Defects of apoptosis are related to the development of cancer, whereas CE abnormalities are associated with barrier abnormalities and ichthyosis.

Key concepts:

  • Keratinocyte apoptosis (occurring in basal layer) is an active and rapid, energy‐dependent, gene‐directed biochemical pathway of defensive cell death that does not require de novo protein synthesis and preserves plasma membrane.

  • Cornification, the keratinocyte differentiation programme (occurring in upper layer), is a slow, coordinated process in space and time, which allows the formation of a layer of dead cells (corneocytes) to create a physical barrier for the skin.

  • The stratum corneum is composed of tightly attached corneocytes with mostly keratin intermediate filaments (KIFs) embedded into a filaggrin matrix.

  • The structural proteins of the CE, including involucrin, loricrin, trichohyalin and the class of small proline‐rich proteins (SPRs), constitute about 7–10% of the mass of the epidermis. These structural proteins together with lipids (ceramides) form the complete barrier.

  • Transglutaminase are Ca2+‐dependent enzymes that catalyse the formation of Nε‐(γ‐glutamyl)lysine bonds between CE structural proteins to confer the characteristic resistance and insolubility to the skin.

  • The junctions responsible for intercellular adhesion and for cohesion of the stratum corneum of the epidermis are of two types: (1) the adherence junctions (connecting the actin cytoskeleton of neighbouring cells) and (2) desmosomes (connecting the keratin filament cytoskeleton of adjacent cells).

  • Proteases are involved in at least three processes in skin differentiation. First, certain cornified envelope precursors require proteolytic processing before cornified envelope formation occurs. Second, the loss of nuclei and mitochondria requires proteolytic processing. Third, desquamation requires proteolysis of the corneodesmosomes.

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

Figure 1.

Apoptosis and terminal differentiation in the epidermis. (A) The genes expressed during skin differentiation and apoptosis are summarized. Apoptosis is restricted only to the lower levels as shown by TUNEL staining and expression of apoptosis‐related genes. (B) A theoretical model of the CE of human foreskin epidermis. The proteins expressed in the epidermis are indicated according to their relative localization. The proteins involved in apoptosis are indicated in red; those related to cornification are indicated in light blue. Death of keratinocytes (CEs) occurs in the upper layers and its defects results in ichthyosis. Death by apoptosis occurs in the basal layer (e.g. after sunburn) and its defects are related to cancer development. (C) Comparison of the amino acid composition of the CE with the amino acid composition of the CE precursors (loricrin, keratins, filaggrin, involucrin, SPRs). As indicated, the most abundant amino acids in the CE are G, S, K, Q and P; these amino acids are also highly represented in loricrin and the SPRs, the two major protein components of the CE (82% and 8% of the epidermal CE, respectively). Adapted from Candi E, Schmidt R and Melino G (2005) The cornified envelope: a model of cell death in the skin. Natural Review. Molecular Cell Biology6(4): 328–340.

Figure 2.

Progressive steps in the formation of CE. (A) Schematic sequence of the different phases, with the related proteins involved, the biological effects and the related diseases. (B) Molecular description of the progressive steps: (1) initiation, (2) formation of the lipid envelope, (3) reinforcement and (4) desquamation. In the initiation phase (1), TG1 and 5 crosslink envoplakin and periplakin under the cell membrane, anchoring them to the desmosome. In the formation of the lipid envelope (2), lipids from the lamellar body, derived from the Golgi, are attached to the already crosslinked proteins and exposed outside the membrane. In the reinforcement phase (3), heavy crosslinking occurs on the desmosome, using keratins, loricrin and SPRs as substrates for TG1 and 3. In the desquamation phase (4), the final crosslinking is catalysed by TG1 on the protein scaffold in addition to lipid deposition. The physical properties of the CE depend on the nature of the substrates and the crosslinks. Adapted from Candi E, Schmidt R and Melino G (2005) The cornified envelope: a model of cell death in the skin. Natural Review. Molecular Cell Biology6(4): 328–340.

Figure 3.

Formation of the cornified envelope: effectors and biological consequences. The differentiation occurs sequentially in steps. Each process is characterized by the expression of proteins and specific diseases can result from abnormalities in these proteins. Biochemical and biophysical properties of the specific proteins involved are the foundation for epidermal properties (e.g. structure stability).

Figure 4.

Transglutaminase family members. (A) TGs are calcium‐dependent enzymes which catalyse the formation of N‐(γ‐glutamyl)lysine bonds between proteins. TG crosslinking activity results in the formation of insoluble protein aggregates. (B) List of the TG family members, tissue distribution, cellular localization and functions. (C) Immunofluorescence staining showing the expression of TG3 and TG5 in human skin.

Figure 5.

Lack of ordered structure in the substrates of skin TGs: loricrin. (A) Schematic diagram of loricrin, showing the three Ω loops, formed by GS residues aligned by the recurrent hydrophobic residues (mostly valine, isoleucine, phenylalanine and tyrosine); Q and K are highlighted. The quantitatively major TG crosslinking sites in loricrin are indicated by the arrows: (1) crosslinks by TG1, (3) crosslinks by TG3. These crosslinks may be intra‐ or interchain and form a highly insoluble structure that is essential for the barrier function of the epidermis. (B) Schematic representation of the loricrin/SPR structural model upon crosslinking by TGs. Due to their peculiar amino acid composition, loricrin/SPR structure is predicted to be ‘spring‐like’: the N‐ and C‐terminal end domains contain most of the Q and K that can be used by TGs as substrates (mechanical resistance). In contrast, the central domain forms a very flexible and non‐ordered structure responsible for the expansion and elasticity of the CE.



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Further Reading

Aberdam D, Candi E, Knight RA and Melino G (2008) miRNAs, ‘stemness’ and skin. Trends in Biochemical Sciences 33(12): 583–591.

Blanpain C and Fuchs E (2009) Epidermal homeostasis: a balancing act of stem cells in the skin. Nature Reviews. Molecular Cell Biology 10(3): 207–217.

Candi E, Schmidt R and Melino G (2005) The cornified envelope: a model of cell death in the skin. Nature Reviews. Molecular Cell Biology 6(4): 328–340. Review.

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

Fuchs E (2007) Scratching the surface of skin development. Nature 445(7130): 834–842.

Getsios S, Huen AC and Green KJ (2004) Working out the strength and flexibility of desmosomes. Nature Reviews. Molecular Cell Biology 5(4): 271–281. Review.

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Melino G, De Laurenzi V, Catani MV et al. (1998) The cornified envelope: a model of cell death in the skin. Results and Problems in Cell Differentiation 24: 175–212.

Nemes Z and Steinert PM (1999) Bricks and mortar of the epidermal barrier. Experimental & Molecular Medicine 31(1): 5–19. Review.

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Steinert PM, Steven AC and Roop DR (1985) The molecular biology of intermediate filaments. Cell 42(2): 411–420. Review.

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Candi, E, Knight, RA, and Melino, G(Dec 2009) Cornification of the Skin: A Non‐apoptotic Cell Death Mechanism. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021583]