Byline: Sigrun. Lange
Peptidylarginine deiminases are a family of calcium-activated enzymes with multifaceted roles in physiological and pathological processes, including in the central nervous system. Peptidylarginine deiminases cause post-translational deimination/citrullination, leading to changes in structure and function of a wide range of target proteins. Deimination can facilitate protein moonlighting, modify protein-protein interaction, cause protein dysfunction and induce inflammatory responses. Peptidylarginine deiminases also regulate the biogenesis of extracellular vesicles, which play important roles in cellular communication through transfer of extracellular vesicle-cargo, e.g., proteins and genetic material. Both peptidylarginine deiminases and extracellular vesicles are linked to a number of pathologies, including in the central nervous system, and their modulation with pharmacological peptidylarginine deiminase inhibitors have shown great promise in several in vitro and in vivo central nervous system disease models. Furthermore, extracellular vesicles derived from mesenchymal stem cells have been assessed for their therapeutic application in central nervous system injury. As circulating extracellular vesicles can be used as non-invasive liquid biopsies, their specific cargo-signatures (including deiminated proteins and microRNAs) may allow for disease 'fingerprinting' and aid early central nervous system disease diagnosis, inform disease progression and response to therapy. This mini-review discusses recent advances in the field of peptidylarginine deiminase and extracellular vesicle research in the central nervous system, focusing on several central nervous system acute injury, degeneration and cancer models.
Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes, with five isozymes identified in human (PAD1, PAD2, PAD3, PAD4 and PAD6), which play multiple roles in physiological and pathological processes, including in the central nervous system (CNS) (Moscarello et al., 1994; Lange et al., 2011, 2014; Nicholas et al., 2014; Ishigami et al., 2015; Caprariello et al., 2018; Faigle et al., 2019; Sancandi et al, 2020). PADs cause post-translational modification of arginine to citrulline (deimination/citrullination), reducing net charge and increasing hydrophobicity of target proteins, leading to changes in protein structure and consequently protein-protein interactions. The different PAD isozymes display tissue-specific expression, with PAD2, PAD3 and PAD4 being the predominant isozymes of the CNS, and PADs furthermore differ in preference for target proteins. Intrinsically disordered proteins are most susceptible for deimination, alongside beta-sheets, and the position of the arginine also plays a role as arginines sitting next to aspartic acid residues are most prone to citrullination/deimination, while arginines flanked by proline or next to glutamic acid residues are rarely deiminated (György et al., 2006; Alghamdi et al., 2019). Deimination can affect a wide range of target proteins, ranging from mitochondrial, cytoplasmic, cytoskeletal and nuclear proteins (e.g., histones) and PADs are furthermore involved in extracellular vesicle (EV) release (Kholia et al., 2015; Lange et al., 2017a). The consequential modification of protein structure, caused by deimination, can lead to changes in protein-protein interactions and also facilitate protein moonlighting, a process which allows the same protein to carry out multiple autonomous and often unrelated functions and therefore contribute to multifaceted use of the same protein according to circumstantial requirements, both temporally and spatially, including in developmental processes, normal physiology and in pathological processes (Jeffrey...