Abstract
Naked mole-rats are long-lived animals that show unusual resistance to hypoxia, cancer and ageing. Protein deimination is an irreversible post-translational modification caused by the peptidylarginine deiminase (PAD) family of enzymes, which convert arginine into citrulline in target proteins. Protein deimination can cause structural and functional protein changes, facilitating protein moonlighting, but also leading to neo-epitope generation and effects on gene regulation. Furthermore, PADs have been found to regulate cellular release of extracellular vesicles (EVs), which are lipid-vesicles released from cells as part of cellular communication. EVs carry protein and genetic cargo and are indicative biomarkers that can be isolated from most body fluids. This study was aimed at profiling deiminated proteins in plasma and EVs of naked mole-rat. Key immune and metabolic proteins were identified to be post-translationally deiminated, with 65 proteins specific for plasma, while 42 proteins were identified to be deiminated in EVs only. Using protein-protein interaction network analysis, deiminated plasma proteins were found to belong to KEEG (Kyoto Encyclopedia of Genes and Genomes) pathways of immunity, infection, cholesterol and drug metabolism, while deiminated proteins in EVs were also linked to KEEG pathways of HIF-1 signalling and glycolysis. The mole-rat EV profiles showed a poly-dispersed population of 50–300 nm, similar to observations of human plasma. Furthermore, the EVs were assessed for three key microRNAs involved in cancer, inflammation and hypoxia. The identification of post-translational deimination of critical immunological and metabolic markers contributes to the current understanding of protein moonlighting functions, via post-translational changes, in the longevity and cancer resistance of naked mole-rats.
Highlights
Peptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes that post-translationally convert arginine into citrulline in target proteins in an irreversible manner
Our findings highlight novel aspects of protein moonlighting via post-translational deimination, including via extracellular vesicles (EVs)-mediated transport
In continuation of the current study, the assessment of changes in deiminated proteins and EV profiles, including protein and genetic EV-cargo, may be of great interest in studies using this unique animal model to further understanding of the hitherto novel and understudied mechanisms involved in cancer and ageing
Summary
Peptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes that post-translationally convert arginine into citrulline in target proteins in an irreversible manner. This can cause structural changes in target proteins and affect protein function, gene regulation and generation of neoepitopes [1,2,3,4,5,6]. PADs and associated protein deimination are crucial players in cancer, autoimmune and neurodegenerative diseases [4,5,6,9], with recent indications for PAD-mediated mechanisms in ageing [10]. Work on EVs has mainly been in the context of human pathologies and recent comparative immunology studies on EVs and EV cargo have been performed [29], including the assessment of deiminated EV protein cargo [30,31,32]
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