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 cross‐links between structural proteins to form the protein part of the CE. Another form of cell death, which has a completely different molecular mechanism and physiological significance, also occurs in the skin: apoptosis. 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 that allows the formation of a dead cells (corneocytes) layer to create a physical barrier for the skin.
  • The stratum corneum is composed of tightly attached corneocytes with mostly keratin intermediate filaments (KIF) 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 that with a complex series of lipids, ceramides, forms the complete barrier.
  • Transglutaminases 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 two types: (1) the adherence junctions (connecting the actin cytoskeleton of neighbouring cells); (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; keratinisation

Figure 1. Apoptosis and terminal differentiation in the epidermis. (a) The genes expressed during skin differentiation and apoptosis are summarised. Apoptosis is restricted only to the lower levels and is characterised by expression of apoptosis‐related genes. The proteins involved in apoptosis are indicated in red; those related to cornification are indicated in blue. (b) A theoretical model of the CE of human foreskin epidermis. The proteins expressed in the epidermis are indicated according to their relative localisation. (c) Comparison of the amino acid composition of the CE with the amino acid composition of 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).
Figure 2. Progressive steps in the formation of CE. Schematic sequence of the different phases, with the related proteins involved and molecular description of the progressive steps: (1) initiation, (2) formation of the lipid envelope, (3) reinforcement, (4) desquamation. In the initiation phase (1), TG1 and 5 cross‐link 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 cross‐linked proteins and exposed outside the membrane. In the reinforcement phase (3), heavy cross‐linking occurs on the desmosome, using keratins, loricrin and SPRs as substrates for TG1 and 3. In the desquamation phase (4), the final cross‐linking 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 on the cross‐links.
Figure 3. Formation of the cornified envelope: effectors and biological consequences. Epidermal properties (structure stability, etc.) are determined by biochemical and biophysical features of the specific proteins. Specific diseases can result from mutations of genes which codify these proteins.
Figure 4. Transglutaminase family members. (a) TGs are calcium‐dependent enzymes which catalyse the formation of N‐(γ‐glutamyl)‐lysine bonds between proteins. TG cross‐linking activity results in the formation of insoluble protein aggregates. (b) List of the TG family members, tissue distribution, cellular localisation 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 cross‐linking sites in loricrin are indicated by the arrows (TG1 and TG3). These cross‐links may be intrachain or interchain and form a highly insoluble structure that is essential for the barrier function of the epidermis. (b) Schematic representation of the loricrin structural model upon cross‐linking by TGs. Owing to its peculiar amino acid composition, loricrin 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 nonordered structure responsible for the expansion and elasticity of the CE.


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Candi, Eleonora, Knight, Richard A, Panatta, Emanuele, Smirnov, Artem, and Melino, Gerry(Nov 2016) Cornification of the Skin: A Non‐apoptotic Cell Death Mechanism. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021583.pub2]