Formation of the cornified envelope

As keratinocytes progress towards the upper epidermis, they undergo a unique process of cell death termed cornification. This involves the crosslinking of keratinocyte proteins such as loricrin and involucrin by transglutaminases and the breakdown of the nucleus and other organelles by intracellular and secreted proteases. This process is strictly regulated by the Ca2+ concentration gradient in the epidermis. Loricrin and involucrin are encoded in ‘Epidermal Differentiation Complex’ linked to a large number of genes encoding nonredundant components of the CE. Keratinocytes produce specialized proteins and lipids which are used to construct the cornified envelope (CE), a heavily crosslinked submembranous layer that confers rigidity to the upper epidermis, allows keratin filaments to attach to any location in the cell membrane and acts as a water-impermeable barrier. The CE has two functional parts: covalently cross-linked proteins (10 nm thick) that comprise the backbone of the envelope and covalently linked lipids (5 nm thick) that coat the exterior. Desmosomal components are crosslinked to the CE to form corneodesmosomes, which bind cornified cells together. Mature terminally differentiated cornified cells consist mostly of keratin filaments covalently attached to the CE embedded in lipid lamellae. The exact composition of the cornified envelope varies between epithelia; the relative amino-acid composition of the proteins used may determine differential mechanical properties.

Summary from Reactome (R-HSA-6809371), read 2026-09-23.