profilaggrin

Profilaggrin is a large cytoplasmic precursor protein that gives rise to filaggrin, a central component of the epidermal barrier. In humans it is encoded by the FLG gene on chromosome 1q21 and is expressed by differentiating keratinocytes in the epidermis, particularly in the stratum granulosum. Profilaggrin is synthesized as a high molecular weight molecule that contains multiple tandem filaggrin repeats (approximately 10–12 copies) within a central region, flanked by N- and C-terminal regulatory domains. During terminal differentiation, profilaggrin is dephosphorylated and proteolytically processed to release filaggrin monomers.

Filaggrin monomers bind to and aggregate keratin intermediate filaments within keratinocytes, promoting the condensation of cells into flattened corneocytes as the stratum corneum forms. Filaggrin is subsequently degraded into smaller fragments and ultimately into free amino acids and derivatives that constitute the natural moisturizing factor (NMF), helping to hydrate the skin and maintain an acidic pH.

Genetic variants in FLG that reduce profilaggrin/filaggrin expression or function are strongly associated with impaired epidermal barrier integrity, dry or ichthyosis vulgaris-like skin, and increased risk of atopic dermatitis and other allergic diseases. Profilaggrin thus plays a central role in epidermal differentiation, barrier formation, and skin hydration.