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

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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.

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.

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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.


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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.

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Correspondence to Gerry Melino.

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Chanarin–Dorfman syndrome

Gaucher disease

lamellar ichthyosis

Netherton syndrome

nonbullous congenital ichthyosiform erythroderma

progressive symmetric erythrokeratodermia

Sjögren–Larsson syndrome

Vohwinkel syndrome

X-linked ichthyosis


μ-calpain (I)

cathepsin D















m-calpain (II)













The Human Intermediate Filament Mutation Database



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.


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.


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.


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.


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


(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).


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.


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


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.


(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.


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.


A protein motif that can bind Ca2+.


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


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


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


Abnormal dryness, especially of the skin or the eye.


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.


The loss of hair.


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


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


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.

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