PAD2-Mediated Citrullination Contributes to Efficient Oligodendrocyte Differentiation and Myelination

Abstract

Summary 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.

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

“…The most prominent functions of OLs is forming the myelin sheath, which is essential for proper neuronal communication and central nervous system function [76]. Notably, PADI2 levels increased during OLs differentiation, and PADI2 acts as a chromatin modifier to promotes oligodendrocyte precursor cell differentiation [77]. Therefore, PADI2 contributes to efficient myelination and motor and cognitive functions.…”

Deimination Protein Profiles in Alligator mississippiensis Reveal Plasma and Extracellular Vesicle-Specific Signatures Relating to Immunity, Metabolic Function, and Gene Regulation

“…PADs have received particular attention due to roles in cancer (20,22,26,27), rheumatoid arthritis (28)(29)(30)(31)(32)(33), multiple sclerosis (34)(35)(36)(37)(38), as well as due to their contribution to skin physiology and diseases (39). PADs have furthermore been shown to play crucial roles in hypoxia and CNS regeneration (40)(41)(42)(43)(44), and roles for PAD2 in promotion of oligodendrocyte differentiation and myelination have been shown (45). PAD-mediated mechanisms have also been related to aging (46,47).…”

Protein citrullination was introduced into animals by horizontal gene transfer from cyanobacteria

“…Via these alterations PADIs regulate fundamental physiological and cellular processes. The bestestablished role of citrullination is in innate immunity, through mediating the release of neutrophil extracellular traps (NETs) 12 but a plethora of studies have shown that PADIs also regulate gene expression, chromatin compaction, nerve myelination, skin homeostasis and the establishment of ground state pluripotency 8,13,14 . Notably, deregulation of PADIs is strongly implicated in the aetiology of a host of pathologies including autoimmunity (rheumatoid arthritis, ulcerative colitis, psoriasis and type I diabetes), neurodegeneration (multiple sclerosis, Alzheimer's and prion diseases) and metastatic cancer 13,[15][16][17][18] .…”

“…Experimental in vivo models of PADI over-expression show that deregulation of citrullination drives the development of multiple sclerosis and cancer 16,20 , while genetic ablation or chemical inhibition of different PADI family members has been shown to mitigate against some the pathologies mentioned above 16,[21][22][23] . Although the underlying mechanism in the above cases is aberrantly high citrullination, loss of PADI activity is also deleterious and has been shown to compromise neurodevelopment, fertility and embryo development 8,14,24 . PADIs have therefore emerged as important therapeutic targets 25 and this has motivated the study of their exquisite regulation by calcium and the physiologically relevant mechanisms of their activation [26][27][28] .…”