Proteins affect most physiological functions in cells and play a key role in maintaining cellular homeostasis. Protein function is tuned at multiple levels, including synthesis and degradation, intracellular localization, and posttranslational modifications (PTMs). PTMs are a key chemical modification for regulating protein biological activity, including protein-folding relevant shifts in electrical charge, protein-protein interactions, and hydrogen bond formation. Such chemical changes can also result in protein unfolding or denaturation. PTMs can target proteins across multiple cellular compartments, including the cell membrane, cytoplasm, nucleus, endoplasmic reticulum, and mitochondria, playing crucial roles in regulating cellular processes, and their dysregulation is linked to the development of numerous diseases. It is well-established that various autoimmune conditions, including multiple sclerosis (MS), are influenced by the PTMs of endogenous proteins. This review adopts an integrated perspective on PTMs, with a particular focus on the citrullination of myelin basic protein (MBP). It moves beyond the traditional view of MS solely as an autoimmune disease, highlighting the broader implications of this initial chemical event, including the role of PAD2, in early disease onset and progression. • PAD2-mediated MBP citrullination is proposed as a candidate early event preceding classic MS lesion formation. • MBP citrullination alters myelin compaction, potentially creating a “prelesional” state in the Normal Appearing White Matter (NAWM). • Aberrant citrullination may bridge the gap between structural myelin damage and T-cell mediated autoimmunity via specific HLA-DRB1 binding. • Understanding the PAD2/MBP axis offers a novel hypothesis for early-stage therapeutic intervention and remyelination strategies.
Orefice et al. (Fri,) studied this question.