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    Peptidylarginine Deiminase Inhibitor Cl-Amidine Attenuates Cornification and Interferes with the Regulation of Autophagy in Reconstructed Human Epidermis

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    Authors
    Cau, Laura
    Takahara, Hidenari
    Thompson, Paul R
    Serre, Guy
    Mechin, Marie-Claire
    Simon, Michel
    UMass Chan Affiliations
    Thompson Lab
    Department of Biochemistry and Molecular Pharmacology
    Document Type
    Journal Article
    Publication Date
    2019-09-01
    Keywords
    Amino Acids, Peptides, and Proteins
    Biochemistry
    Cell Biology
    Cells
    Cellular and Molecular Physiology
    Dermatology
    Enzymes and Coenzymes
    Physiological Processes
    
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    Link to Full Text
    https://doi.org/10.1016/j.jid.2019.02.026
    Abstract
    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.
    Source

    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

    DOI
    10.1016/j.jid.2019.02.026
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/29410
    PubMed ID
    30878672
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    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1016/j.jid.2019.02.026
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