title: Lowering relative humidity level increases epidermal protein deimination and drives human filaggrin breakdown.
abstract: BACKGROUND
  Deimination (also known as citrullination), the conversion of arginine in a protein to citrulline, is catalyzed by a family of enzymes called peptidylarginine deiminases (PADs). Three PADs are expressed in the epidermis, one of their targets being filaggrin. Filaggrin plays a central role in atopic dermatitis and is a key protein for the epidermal barrier. It aggregates keratins and is cross-linked to cornified envelopes. Following its deimination, it is totally degraded to release free amino acids, contributing to the natural moisturizing factor (NMF). The mechanisms controlling this multistep catabolism in human are unknown.
  
  
  OBJECTIVE
  To test whether external humidity plays a role, and investigate the molecular mechanisms involved.
  
  
  METHODS
  Specimens of reconstructed human epidermis (RHEs) produced in humid or dry conditions (>95% or 30-50% relative humidity) were compared.
  
  
  RESULTS
  RHEs produced in the dry condition presented structural changes, including a thicker stratum corneum and a larger amount of keratohyalin granules. The transepidermal water loss and the stratum corneum pH were decreased whereas the quantity of NMF was greater. This highly suggested that filaggrin proteolysis was up-regulated. The expression/activity of the proteases involved in filaggrin breakdown did not increase while PAD1 expression and the deimination rate of proteins, including filaggrin, were drastically enhanced. Partial inhibition of PADs with Cl-amidine reversed the effect of dryness on filaggrin breakdown.
  
  
  CONCLUSIONS
  These results demonstrate the importance of external humidity in the control of human filaggrin metabolism, and suggest that deimination plays a major role in this regulation.
authors.affiliation: UDEAR, Institut National de la Santé Et de la Recherche Médicale, Université de Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique, Toulouse, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Cau
authors.affiliation: UDEAR, Institut National de la Santé Et de la Recherche Médicale, Université de Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique, Toulouse, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Pendaries
authors.affiliation: UDEAR, Institut National de la Santé Et de la Recherche Médicale, Université de Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique, Toulouse, France; Plateau de Génomique GeT-Purpan, Genotoul, Toulouse, France.
authors.forename: Emeline
authors.initials: E
authors.lastname: Lhuillier
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.affiliation: UDEAR, Institut National de la Santé Et de la Recherche Médicale, Université de Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique, Toulouse, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Serre
authors.affiliation: Department of Applied Biological Resource Sciences, School of Agriculture, University of Ibaraki, Ibaraki, Japan.
authors.forename: Hidenari
authors.initials: H
authors.lastname: Takahara
authors.affiliation: UDEAR, Institut National de la Santé Et de la Recherche Médicale, Université de Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique, Toulouse, France.
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Méchin
authors.affiliation: UDEAR, Institut National de la Santé Et de la Recherche Médicale, Université de Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique, Toulouse, France. Electronic address: michel.simon@inserm.fr.
authors.forename: Michel
authors.initials: M
authors.lastname: Simon
mesh_terms: D000328:Adult; D001120:Arginine / Q000737:chemistry; D002454:Cell Differentiation; D002956:Citrulline / Q000737:chemistry; D002980:Climate; D003432:Cross-Linking Reagents / Q000737:chemistry; D003876:Dermatitis, Atopic / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D005260:Female; D000091344:Filaggrin Proteins; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D006813:Humidity; D006863:Hydrogen-Ion Concentration; D006867:Hydrolases / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000737:chemistry*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D007633:Keratins / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D000076342:Protein-Arginine Deiminases; D012867:Skin / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D005456:Fluorescent Dyes; D007381:Intermediate Filament Proteins; D002956:Citrulline; D007633:Keratins; D001120:Arginine; D011503:Transglutaminases; D006867:Hydrolases; D000076342:Protein-Arginine Deiminases
keywords: Atopic dermatitis; Citrullination; Posttranslational modification; Protein deiminase; Proteolysis; Skin