Title

Lowering relative humidity level increases epidermal protein deimination and drives human filaggrin breakdown

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Thompson Lab

Publication Date

5-1-2017

Document Type

Article

Disciplines

Biochemistry | Dermatology | Enzymes and Coenzymes | Skin and Connective Tissue Diseases

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.

Keywords

Atopic dermatitis, Citrullination, Posttranslational modification, Protein deiminase, Proteolysis, Skin

DOI of Published Version

10.1016/j.jdermsci.2017.02.280

Source

J Dermatol Sci. 2017 May;86(2):106-113. doi: 10.1016/j.jdermsci.2017.02.280. Epub 2017 Feb 20. Link to article on publisher's site

Journal/Book/Conference Title

Journal of dermatological science

Related Resources

Link to Article in PubMed

PubMed ID

28242341