Laura Cau1, Valérie Pendaries1, Emeline Lhuillier2, Paul R Thompson3, Guy Serre1, Hidenari Takahara4, Marie-Claire Méchin1, Michel Simon5. 1. UDEAR, Institut National de la Santé Et de la Recherche Médicale, Université de Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique, Toulouse, France. 2. 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. 3. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA. 4. Department of Applied Biological Resource Sciences, School of Agriculture, University of Ibaraki, Ibaraki, Japan. 5. 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.
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. CONCLUSION: 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.
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. CONCLUSION: These results demonstrate the importance of external humidity in the control of humanfilaggrin metabolism, and suggest that deimination plays a major role in this regulation.
Authors: Laura Cau; Hidenari Takahara; Paul R Thompson; Guy Serre; Marie-Claire Méchin; Michel Simon Journal: J Invest Dermatol Date: 2019-03-13 Impact factor: 8.551
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