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Deimination is regulated at multiple levels including auto-deimination of peptidylarginine deiminases

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Abstract

Peptidylarginine deiminases (PADs) catalyze deimination, converting arginyl to citrullyl residues. Only three PAD isotypes are detected in the epidermis where they play a crucial role, targeting filaggrin, a key actor for the tissue hydration and barrier functions. Their expression and activation depends on the keratinocyte differentiation state. To investigate this regulation, we used primary keratinocytes induced to differentiate either by increasing cell-density or by treatment with vitamin D. High cell-density increased PAD1 and 3, but not PAD2, at the mRNA and protein levels, and up-regulated protein deimination. By contrast, vitamin D increased PAD1–3 mRNA amounts, with distinct kinetics, but neither the proteins nor the deimination rate. Furthermore, auto-deimination was shown to decrease PAD activity, increasing the distances between the four major amino acids of the active site. In summary, deimination can be regulated at multiple levels: transcription of the PADI genes, translation of the corresponding mRNAs, and auto-deimination of PADs.

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Acknowledgments

We thank C. Pons for her excellent technical assistance, the staff of the “Laboratoire de Biologie Cellulaire Cutanée du CERPER”, especially I. Cerutti, M. J. Haure and S. Julié, for their technical advice, the sequencing and genotyping facility of the IFR150 at Toulouse-Purpan, particularly C. Offer and H. Brun for their precious high efficiency, and the histological facility at Toulouse-Purpan, especially F. Capilla for her technical advice. We are indebted to Dr A Ishigami (Chiba, Japan) for the anti-PAD2 antibody and to Drs H Palmer and G. Carmeliet (Cancer Research UK Cambridge Research Institute, Cambridge, UK) for providing us with skin sections of VDR-null mice and control littermates. We would also particularly like to thank N. Mattiuzzo for his technical bio-informatics suggestions for performing VDRE sequences analysis, and Drs M. Sebbag and C.-Y. Hsu for their advice and helpful discussions. This work was supported by grants from the “Centre National de la Recherche Scientifique” (CNRS), the “Société Française de Dermatologie” and the “Centre Européen de Recherche sur la Peau et les Epithéliums de Revêtement” (CERPER, Toulouse, France) and by the “Institut National de la Santé et de la Recherche Médicale” (INSERM).

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  1. CNRS-University of Toulouse III, UMR5165, Institut Fédératif de Recherche 150 (INSERM-CNRS-Université paul Sabatier-Centre Hospitalier Universitaire de Toulouse), CHU Purpan, Place du Dr Baylac TSA40031, 31059, Toulouse Cedex 9, France

    Marie-Claire Méchin, Fanny Coudane, Véronique Adoue, Jacques Arnaud, Guy Serre & Michel Simon

  2. Centre Européen de Recherche sur la Peau et les Epithéliums de Revêtement (CERPER), Pierre Fabre Dermo-Cosmétique, Toulouse, France

    Hélène Duplan, Marie Charveron & Anne-Marie Schmitt

  3. Department of Applied Biological Resource Sciences, School of Agriculture, University of Ibaraki, Ibaraki, Japan

    Hidenari Takahara

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  1. Marie-Claire Méchin
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Correspondence to Michel Simon.

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Méchin, MC., Coudane, F., Adoue, V. et al. Deimination is regulated at multiple levels including auto-deimination of peptidylarginine deiminases. Cell. Mol. Life Sci. 67, 1491–1503 (2010). https://doi.org/10.1007/s00018-010-0262-5

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