Peptidylarginine Deiminases—Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release?

Figures

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  Figure 1. STRING analysis (https://string-db.org/) showing putative binding partners (STRING combined score >0.4) of PAD2 and PAD4, identified and found to be present in exosomes and microvesicles EMVs based on a search by gene symbol in the Vesiclepedia protein data set. Lines between nodes represent the following: Green line = text mining; Blue line = from curated database; Pink line = experimentally determined.

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  Figure 2. Mechanisms of peptidylarginine deiminases PADs) in central nervous system (CNS injury and neurodegenerative pathologies and the proposed effect of PAD-inhibitors. Upon CNS injury (hypoxic ischaemic encephalopathy, HIE), Ca2+ entry is facilitated via the reversal of the Na+/Ca2+ exchanger due to over activation of the Na+/H+ exchanger (NHE). Ca2+ entry can also be facilitated due to membranolytic pathways including the complement membrane attack complex (MAC) and perforin. Increased cytosolic Ca2+ triggers the neurotoxic cascade, which includes activation of the Ca2+ dependent PAD enzymes. Neurodegenerative disease mutations cause protein aggregation and impaired calcium buffering, which activates the downstream PAD-cascade. Both in CNS acute injury and neurodegeneration, PAD activation causes protein deimination and further protein misfolding, affecting cell motility, autophagy, phagoptosis, and mictochondrial function, leading to neurotoxic events. Deiminated neo-epitopes and leakage of deiminated proteins from dying cells contribute to neuroinflammation that in turn may upregulate TNFα, which causes nuclear translocation of PADs, leading to histone deimination and also…