title: Regulatory role for the profilaggrin N-terminal domain in epidermal homeostasis.
abstract: It is well known that profilaggrin, after its release from keratohyalin granules through dephosphorylation, becomes enzymatically processed into individual filaggrin monomers. The roles for filaggrin monomers in aggregating keratin filaments, as a component of the cornified cell envelope, and as a source of natural moisturizing factor are well established. A specific N-terminal fragment, called the PF-AB domain, becomes proteolytically released as well, but much less is known about its functional role in epidermal development. Here, the functional role of profilaggrin N-terminal (PF-N) domain was addressed by overexpressing three overlapping fragments from a lentiviral expression vector in the epidermis of living skin equivalents. The PF-N domain expression impaired the epidermal development through reducing keratinocyte proliferation and impairing differentiation. The expression of well-known differentiation markers profilaggrin, loricrin, and keratin 10 was considerably downregulated in PF-N domain overexpressing-skin equivalents. The activation of caspase 14 was also substantially affected. In contrast, total silencing of profilaggrin expression, obtained with a lentiviral miR vector, resulted in a hyperproliferative epidermis. We propose a hypothesis that profilaggrin AB domain provides a key feedback mechanism that controls epidermal homeostasis.
authors.affiliation: Biosciences, Unilever R&D, Trumbull, Connecticut, USA. Electronic address: sirpa.aho@unilever.com.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Aho
authors.affiliation: Biosciences, Unilever R&D Port Sunlight, Bebington, UK.
authors.forename: Clive R
authors.initials: CR
authors.lastname: Harding
authors.affiliation: Biosciences, Unilever R&D, Trumbull, Connecticut, USA.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Biosciences, Unilever R&D, Trumbull, Connecticut, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Meldrum
authors.affiliation: Biosciences, Unilever R&D, Trumbull, Connecticut, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Bosko
mesh_terms: D000328:Adult; D053456:Caspase 14 / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D000091344:Filaggrin Proteins; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D053550:Keratin-10 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; C064554:loricrin; D053550:Keratin-10; D053456:Caspase 14