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Cell Rep. 2019 Apr 23;27(4):1090-1102.e10. doi: 10.1016/j.celrep.2019.03.108.

PAD2-Mediated Citrullination Contributes to Efficient Oligodendrocyte Differentiation and Myelination.

Author information

1
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
2
Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York, New York, NY, USA.
3
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029.
4
Department of Proteomics, the Novo Nordisk Foundation Center for Protein Research, Faculty of Heath Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
5
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
6
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Cancer Cell Biology Lab, Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510157, Chile.
7
Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
8
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Ming Wai Lau Centre for Reparative Medicine, Stockholm Node, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: goncalo.castelo-branco@ki.se.

Abstract

Citrullination, the deimination of peptidylarginine residues into peptidylcitrulline, has been implicated in the etiology of several diseases. In multiple sclerosis, citrullination is thought to be a major driver of pathology through hypercitrullination and destabilization of myelin. As such, inhibition of citrullination has been suggested as a therapeutic strategy for MS. Here, in contrast, we show that citrullination by peptidylarginine deiminase 2 (PAD2) contributes to normal oligodendrocyte differentiation, myelination, and motor function. We identify several targets for PAD2, including myelin and chromatin-related proteins, implicating PAD2 in epigenomic regulation. Accordingly, we observe that PAD2 inhibition and its knockdown affect chromatin accessibility and prevent the upregulation of oligodendrocyte differentiation genes. Moreover, mice lacking PAD2 display motor dysfunction and a decreased number of myelinated axons in the corpus callosum. We conclude that citrullination contributes to proper oligodendrocyte lineage progression and myelination.

KEYWORDS:

PAD2; Padi2; SILAC; chromatin accessibility; citrullination; deamination; multiple sclerosis; myelin; oligodendrocytes; proteomics

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