FILAGGRIN

Filaggrin is a structural protein of the epidermis encoded by the FLG gene. In differentiating keratinocytes it is produced as profilaggrin, a large repetitive precursor stored in keratohyalin granules of the stratum granulosum. Through proteolytic processing, profilaggrin is cleaved to individual filaggrin monomers that bind and bundle keratin intermediate filaments, promoting the condensation of the cytoskeleton and the formation of the flattened corneocytes that make up the stratum corneum.

Filaggrin monomers are further degraded during late differentiation to smaller peptides and free amino acids, which together form the natural moisturizing factor (NMF). These breakdown products help maintain skin hydration, contribute to the acidic pH of the stratum corneum, and support barrier function.

Genetic variants in FLG, particularly loss-of-function mutations, reduce filaggrin production and are strongly linked to ichthyosis vulgaris and to increased risk of atopic dermatitis and other allergic diseases. Individuals with biallelic FLG mutations typically have more severe barrier dysfunction and higher transepidermal water loss.

FLG is located in the epidermal differentiation complex on chromosome 1q21 and is expressed in keratinocytes during later stages of epidermal differentiation. Proper processing by skin-specific proteases (including caspase-14 and bleomycin hydrolase) and post-translational modifications influence filaggrin function and NMF production, underscoring its central role in skin barrier homeostasis.