Epithelial barrier function: assembly and structural features of the cornified cell envelope

Abstract

Terminally differentiating stratified squamous epithelial cells assemble a specialized protective barrier structure on their periphery termed the cornified cell envelope (CE). It is composed of numerous structural proteins that become cross-linked by several transglutaminase enzymes into an insoluble macromolecular assembly. Several proteins are involved in the initial stages of CE assembly, but only certain proteins from a choice of more than 20 different proteins are used in the final stages of CE reinforcement, apparently to meet tissue-specific requirements. In addition, a variable selection of proteins may be upregulated in response to genetic defects of one of the CE proteins or tissue injury, in an effort to maintain an effective barrier. Additionally, in the epidermis and hair fiber cuticle, a layer of lipids is covalently attached to the proteins, which provides essential water barrier properties. Here we describe our current understanding of CE structure, a possible mechanism of its assembly, and various disorders that cause a defective barrier.

Specific Citrullination Causes Assembly of a Globular S100A3 Homotetramer

“…In terrestrial animals, Ca 2ϩ is an essential divalent cation in the formation of the epithelial protective barrier by superficial tissues that are exposed to the external environment (8). A specialized protein structure termed the cornified cell envelope (CE) 2 encapsulates the corneocytes of mammalian skin epidermis and hair fiber cuticle.…”

“…profilaggrin and trichohyalin) (10). Most of these genes were reported to be coordinately expressed during epithelial terminal differentiation, and the translation products were incorporated to the CE (8); however, the functional role of S100 proteins and S100-like domains responsible for regulating the intracellular Ca 2ϩ ion in the epithelial cornifying processes is poorly understood.…”

“…Several epithelial protein barrier components containing Ca 2ϩ -binding domains have been reported to be natural substrates of PAD (the mature filaggrin subunit, proteolytically processed from profilaggrin (13)) or of transgutaminase (S100A7, S100A10, and S100A11 (14,15)) in skin epidermis or of both these enzymes (trichohyalin (16,17)) in hair follicles. It has been proposed that the Ca 2ϩ ions bound to these proteins are presented to the Ca 2ϩ -dependent proteinmodifying enzymes (8,11); however, more direct evidence is necessary to support this notion.…”

“…The flattened cuticular layers composed of the mechanically tough but dead cells confer the physical and chemical barrier function (23); however, little is known about the terminal differentiation processes of this specialized epithelium equipped with a thick protein envelope (8). Although our previous investigation suggested that S100A3 is closely associated with the cuticular differentiation within the hair follicle (24 -26), the very low affinity of S100A3 for Ca 2ϩ (K d ϭ 4 -30 mM) (20,21) cast doubt on its supposed role as an intracellular Ca 2ϩ -modulating protein.…”

Targeted deletion of the sciellin gene resulted in normal development and maturation

“…The major structural framework of these cells is the cornified envelope (Hashimoto, 1969;Brody, 1969), which is a complex mixture of proteins cross-linked primarily by e(c-glutamyl) lysine bonds (Gallicano et al, 1999;DiColandrea et al, 2000;Ruhrberg et al, 1996;Steinert and Marekov, 1995;Candi et al, 1998;Marshall et al, 2001;Kalinin et al, 2002;Rice and Green, 1977;. Although the function of the various components is incompletely understood, it has been proposed that the plakin proteins and involucrin form the initial scaffolding in the granular layer and these are cross-linked by transglutaminase 1 at the inner side of plasma membrane (Kalinin et al, 2001(Kalinin et al, , 2002. Lipids are extruded in lamellar bodies into the intracellular space (Landmann, 1980(Landmann, , 1986 and are cross-linked by transglutaminase to involucrin and other scaffolding proteins Swartzendruber et al, 1987;Marekov and Steinert, 1998).…”