Peptidylarginine Deiminase Inhibitor Cl-Amidine Attenuates Cornification and Interferes with the Regulation of Autophagy in Reconstructed Human Epidermis
Department of Biochemistry and Molecular Pharmacology; Thompson Lab
Amino Acids, Peptides, and Proteins | Biochemistry | Cell Biology | Cells | Cellular and Molecular Physiology | Dermatology | Enzymes and Coenzymes | Physiological Processes
Deimination, a post-translational modification catalyzed by a family of enzymes called peptidylarginine deiminases (PADs), is the conversion of arginine into citrulline residues in a protein. Deimination has been associated with numerous physiological and pathological processes. Our aim was to study its implication in the homeostasis of human epidermis, where three PADs are expressed, namely PAD1, 2, and 3. Three-dimensional reconstructed human epidermis (RHEs) were treated for 2 days with increased concentrations (0-800 muM) of Cl-amidine, a specific PAD inhibitor. Cl-amidine treatments inhibited deimination in a dose-dependent manner and were not cytotoxic for keratinocytes. At 800 muM , Cl-amidine was shown to reduce deimination by half, alter keratinocyte differentiation, decrease the number of corneocyte layers, significantly increase the number of transitional cells, induce clustering of mitochondria and of heterogeneous vesicles in the cytoplasm of granular keratinocytes, and upregulate the expression of autophagy proteins, including LC3-II, sestrin-2, and p62/SQSTM1. LC3 and PADs were further shown to partially co-localize in the upper epidermis. These results demonstrated that Cl-amidine treatments slow down cornification and alter autophagy in the granular layer. They suggest that PAD1 and/or PAD3 play a role in the constitutive epidermal autophagy process that appears as an important step in cornification.
DOI of Published Version
J Invest Dermatol. 2019 Sep;139(9):1889-1897.e4. doi: 10.1016/j.jid.2019.02.026. Epub 2019 Mar 13. Link to article on publisher's site
The Journal of investigative dermatology
Cau L, Takahara H, Thompson PR, Serre G, Mechin M, Simon M. (2019). Peptidylarginine Deiminase Inhibitor Cl-Amidine Attenuates Cornification and Interferes with the Regulation of Autophagy in Reconstructed Human Epidermis. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1016/j.jid.2019.02.026. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1639