Abstract 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 Ca 2+ -dependent enzymes that catalyse the formation of N ϵ -(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.

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