Deimination and Peptidylarginine Deiminases in Skin Physiology and Diseases.

Marie-Claire Méchin,Hidenari Takahara,Michel Simon

doi:10.3390/ijms21020566

Abstract

Deimination, also known as citrullination, corresponds to the conversion of the amino acid arginine, within a peptide sequence, into the non-standard amino acid citrulline. This post-translational modification is catalyzed by a family of calcium-dependent enzymes called peptidylarginine deiminases (PADs). Deimination is implicated in a growing number of physiological processes (innate and adaptive immunity, gene regulation, embryonic development, etc.) and concerns several human diseases (rheumatoid arthritis, neurodegenerative diseases, female infertility, cancer, etc.). Here, we update the involvement of PADs in both the homeostasis of skin and skin diseases. We particularly focus on keratinocyte differentiation and the epidermal barrier function, and on hair follicles. Indeed, alteration of PAD activity in the hair shaft is responsible for two hair disorders, the uncombable hair syndrome and a particular form of inflammatory scarring alopecia, mainly affecting women of African ancestry.

Highlights

Deimination or citrullination corresponds to the conversion of the amino acid arginine within a peptide sequence into the non-standard amino acid citrulline
We identified two hair disorders due to mutations in the PAD3 encoding gene: A rare hair shaft dysplasia called uncombable hair syndrome (UHS; OMIM#191480, #617251, and #617252) [22], and a particular form of alopecia, the Central Centrifugal Cicatricial Alopecia (CCCA, OMIM%618352), affecting up to 5% of women of African ancestry and the most common type of primary scarring alopecia [23]
PAD1 is present in all layers of the epidermis from the basal layer to the superficial stratum corneum with an increasing expression from the basal to the granular keratinocytes

Summary

Introduction

Deimination or citrullination corresponds to the conversion of the amino acid arginine within a peptide sequence into the non-standard amino acid citrulline. Deimination is distinct from the formation of free citrulline through the action of nitric oxide synthases on free arginine. Instead, it is a post-translational modification of proteins, catalyzed by a family of calcium-dependent enzymes, called peptidylarginine deiminases or protein-arginine deiminases (PADs, EC3.5.3.15). 1-α, 25-dihydroxyvitamin D3 induces the expression of PAD mRNA in keratinocytes [16,17], and auto-deimination of PADs changes their tertiary structure and interferes with their enzymatic activity or protein-protein interactions [16,18,19]. We have identified several substrates in the epidermis and hair follicles, including keratins and S100-fused type proteins, and have characterized the effects of their deimination. We identified two hair disorders due to mutations in the PAD3 encoding gene: A rare hair shaft dysplasia called uncombable hair syndrome (UHS; OMIM#191480, #617251, and #617252) [22], and a particular form of alopecia, the Central Centrifugal Cicatricial Alopecia (CCCA, OMIM%618352), affecting up to 5% of women of African ancestry and the most common type of primary scarring alopecia [23]

Expression and Role of PADs in Normal Skin

PADs and Deiminated Proteins in the Epidermis

PADs and Deiminated Proteins in Hair Follicles

PAD Defects and Skin Diseases

Findings

Conclusions