Function of Filaggrin and Caspase-14 in Formation and Maintenance of the Epithelial Barrier

Stratifi ed epithelia line all external and internal body surfaces of mammals and function to protect us from water loss, environmental insults, chemical damage, and infection. This protective barrier is composed of a complex mixture of structural proteins and specialized lipids that together form the anuclear squames of the stratum corneum. Filaggrin and caspase-14 are two genes expressed in the granular layer of epidermis and other stratified keratinizing epithelia. Filaggrin is a keratin-binding protein present in the lower layers of the stratum corneum which plays a key role in barrier function. Filaggrin is synthesized as a large precursor, profi laggrin, that undergoes specific processing during keratinocyte differentiation to produce filaggrin. In the middle and upper layers of the stratum corneum, fi laggrin is degraded to free amino acids which have several functions including water adsorption. Recent work has shown that loss-offunction mutations in the fi laggrin (FLG) gene cause the dry skin disease ichthyosis vulgaris. Similar FLG variants are strongly associated with the common infl ammatory skin disease atopic dermatitis (eczema). Current studies suggest that~50% of European patients with moderate to severe eczema carry one or more FLG null alleles. Caspase-14 is a member of the caspase family of aspartate-specifi c proteases that is co-expressed with fiwithin the epidermis. Recent work has shown that it functions both as a profi laggrin protease and protects against UV irradiation. These studies emphasize the importance of proteases in regulating profi laggrin/fi laggrin and caspase-14 function, and their common and overlapping roles in epithelial barrier homeostasis. (Dermatol Sinica 27: 1-14, 2009)