title: Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin.
abstract: Caspase-14 is a protease that is mainly expressed in suprabasal epidermal layers and activated during keratinocyte cornification. Caspase-14-deficient mice display reduced epidermal barrier function and increased sensitivity to UVB radiation. In these mice, profilaggrin, a protein with a pivotal role in skin barrier function, is processed correctly to its functional filaggrin (FLG) repeat unit, but proteolytic FLG fragments accumulate in the epidermis. In wild-type stratum corneum, FLG is degraded into free amino acids, some of which contribute to generation of the natural moisturizing factors (NMFs) that maintain epidermal hydration. We found that caspase-14 cleaves the FLG repeat unit and identified two caspase-14 cleavage sites. These results indicate that accumulation of FLG fragments in caspase-14(-/-) mice is due to a defect in the terminal FLG degradation pathway. Consequently, we show that the defective FLG degradation in caspase-14-deficient skin results in substantial reduction in the amount of NMFs, such as urocanic acid and pyrrolidone carboxylic acid. Taken together, we identified caspase-14 as a crucial protease in FLG catabolism.
authors.affiliation: Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
authors.forename: Esther
authors.initials: E
authors.lastname: Hoste
authors.forename: Patrick
authors.initials: P
authors.lastname: Kemperman
authors.forename: Michael
authors.initials: M
authors.lastname: Devos
authors.forename: Geertrui
authors.initials: G
authors.lastname: Denecker
authors.forename: Sanja
authors.initials: S
authors.lastname: Kezic
authors.forename: Nico
authors.initials: N
authors.lastname: Yau
authors.forename: Barbara
authors.initials: B
authors.lastname: Gilbert
authors.forename: Saskia
authors.initials: S
authors.lastname: Lippens
authors.forename: Philippe
authors.initials: P
authors.lastname: De Groote
authors.forename: Ria
authors.initials: R
authors.lastname: Roelandt
authors.forename: Petra
authors.initials: P
authors.lastname: Van Damme
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.forename: Richard B
authors.initials: RB
authors.lastname: Presland
authors.forename: Hidenari
authors.initials: H
authors.lastname: Takahara
authors.forename: Gerwin
authors.initials: G
authors.lastname: Puppels
authors.forename: Peter
authors.initials: P
authors.lastname: Caspers
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: Wim
authors.initials: W
authors.lastname: Declercq
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D053456:Caspase 14 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism; D005260:Female; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D059748:Proteolysis; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*; D012867:Skin / Q000378:metabolism* / Q000528:radiation effects; D012879:Skin Physiological Phenomena; D014466:Ultraviolet Rays; D014560:Urocanic Acid / Q000378:metabolism*
chemical_list: D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D053456:Caspase 14; D014560:Urocanic Acid; D011761:Pyrrolidonecarboxylic Acid