title: SASPase regulates stratum corneum hydration through profilaggrin-to-filaggrin processing.
abstract: The stratum corneum (SC), the outermost layer of the epidermis, acts as a barrier against the external environment. It is hydrated by endogenous humectants to avoid desiccation. However, the molecular mechanisms of SC hydration remain unclear. We report that skin-specific retroviral-like aspartic protease (SASPase) deficiency in hairless mice resulted in dry skin and a thicker and less hydrated SC with an accumulation of aberrantly processed profilaggrin, a marked decrease of filaggrin, but no alteration in free amino acid composition, compared with control hairless mice. We demonstrated that recombinant SASPase directly cleaved a linker peptide of recombinant profilaggrin. Furthermore, missense mutations were detected in 5 of 196 atopic dermatitis (AD) patients and 2 of 28 normal individuals. Among these, the V243A mutation induced complete absence of protease activity in vitro, while the V187I mutation induced a marked decrease in its activity. These findings indicate that SASPase activity is indispensable for processing profilaggrin and maintaining the texture and hydration of the SC. This provides a novel approach for elucidating the complex pathophysiology of atopic dry skin.
authors.affiliation: Medical Top Track (MTT) Program, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. tmatsui@icems.kyoto-u.ac.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Matsui
authors.forename: Kenichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Akiharu
authors.initials: A
authors.lastname: Kubo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawasaki
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Ebihara
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hata
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanahashi
authors.forename: Shizuko
authors.initials: S
authors.lastname: Ichinose
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
authors.forename: Jun
authors.initials: J
authors.lastname: Kudoh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amagai
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D003876:Dermatitis, Atopic / Q000201:enzymology / Q000235:genetics; D004817:Epidermis / Q000201:enzymology / Q000502:physiology*; D000091344:Filaggrin Proteins; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008812:Mice, Hairless; D020125:Mutation, Missense; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014867:Water / Q000378:metabolism
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D011498:Protein Precursors; D011994:Recombinant Proteins; D014867:Water; D016282:Aspartic Acid Endopeptidases; C503513:skin aspartic protease, human