Definition of Keratinization
Keratinization (also called cornification or cornified envelope formation) is a specialized form of programmed cell death restricted to keratinocytes that generates the stratum corneum—the outermost protective layer of skin composed of dead, protein-filled cells (corneocytes) surrounded by crosslinked proteins and lipids. 1
Core Biological Process
Keratinization represents a unique terminal differentiation pathway where keratinocytes undergo systematic transformation from living basal cells into dead corneocytes that form the skin's protective barrier. 1 This process differs fundamentally from apoptosis or necrosis, as the resulting corneocytes cannot undergo stress-induced cell death, making cornification a true programmed cell death pathway rather than simple terminal differentiation. 1
Structural Components Generated
The keratinization process produces specific structural elements:
Protein components: Keratin intermediate filaments fill the cytoplasm after organelle removal, providing mechanical strength, while specialized proteins (loricrin, involucrin, filaggrin, SPR, SP100) are crosslinked to form the cornified envelope. 1, 2
Lipid components: Fatty acids and ceramides are extruded into extracellular spaces and covalently attached to envelope proteins, creating water repellence and barrier impermeability. 1, 3
Final structure: The stratum corneum consists of these dead keratinocytes (corneocytes) containing this protein-lipid amalgam, conferring structural stability, mechanical resistance, elasticity, and water repellence to skin. 1
Key Enzymatic Machinery
The biochemical execution of keratinization depends on specific enzymes:
Transglutaminases (TG-1, TG-3, TG-5): Catalyze the crosslinking reactions that create the insoluble protein envelope. 1, 3
Caspase-14: Plays a critical role in proper stratum corneum formation; mice lacking caspase-14 show altered stratum corneum composition, reduced hydration, increased water loss, and heightened UV sensitivity. 1
Functional Characteristics
Keratinization can be formally defined by three criteria:
Cell-type restriction: Occurs exclusively in keratinocytes. 1
Functional linkage: Directly generates the stratum corneum of the epidermis. 1
Enzymatic dependence: Can be altered (though not completely blocked) by inhibiting transglutaminases or caspase-14. 1
Physiological Significance
This process provides essential barrier functions including protection from UV radiation, prevention of water loss (maintaining homeostasis), mechanical protection, and defense against external xenobiotics, allergens, and microorganisms. 1 The stratum corneum represents approximately the outermost 0.05-2mm of skin thickness depending on anatomical location. 1
Distinction from Other Cell Death Pathways
Unlike apoptosis or necrosis affecting basal epidermal cells responding to injury (such as UV irradiation), keratinization is a continuous physiological process in the external epidermal layer. 1 The process involves partial activation of cell death executioners (notably caspases) but maintains anti-apoptotic and anti-necroptotic pathways to prevent premature cell death during terminal differentiation. 2