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Figure 1. Profilaggrin processing during terminal differentiation of the epidermis. Within the granular layer, profilaggrin is stored in an inactive and insoluble form within keratohyalin granules. In response to an increase in Ca2+ levels, the keratohyalin granules degranulate and profilaggrin is dephosphorylated and proteolysed in a multistep process into free filaggrin monomers by a variety of proteases including matriptase, prostasin and probably kallikrein 5 (see text for details). Following cleavage from the filaggrin monomers, the N-terminal head domain undergoes nuclear translocation and further degradation into the A and B domains. In the cornified layer (stratum corneum), the released filaggrin monomers bind directly to keratin filaments, causing their collapse into thickened and aggregated keratin filaments, which has the effect of condensing the keratinocyte cytoskeleton. Condensation of the cytoskeleton is followed by crosslinking with transglutaminases and modification by PADs to form an insoluble keratin matrix. Together with lipids and other cornified-layer proteins, this ultimately forms the so-called `skin barrier', which prevents water loss through the skin as well as the unwanted entry of molecules such as allergens. Filaggrin undergoes subsequent degradation by a variety of proteases, including caspase 14, into free amino acids and derivatives such as UCA and PCA -these are collectively referred to as NMF, which contributes to skin hydration and possibly to UV protection. IF: Intermediate filament; NMF: Natural moisturising factor; PAD: Peptidylarginine deiminase; PCA: Pyrrolidone carboxylic acid; UCA: Urocanic acid; TGM: Transglutaminase. Reproduced with permission from [48].
(Figure omitted. See article PDF.)
Figure 2. Role of filaggrin in maintaining skin barrier function. UCA: Urocanic acid; UVB: Ultraviolet B. Reproduced with permission from [49].
(Figure omitted. See article PDF.)
Filaggrin
Filaggrin is a S100 calcium-binding protein with key roles in establishing the skin's epidermal barrier function. It is expressed in the skin and in the nose up to the transitional epithelium as well as the keratinized epithelium of the conjunctiva and oral cavity. Filaggrin is not found on deeper mucosal surfaces of the nose, lung or gut. Its gene is encoded on chromosome 1q21 as part of the epidermal differentiation complex (EDC). The EDC is a cluster of genes crucial to formation of the stratum corneum of the epidermis. Filaggrin is secreted as a phosphorylated polypeptide (profilaggrin), which is predominantly found in...