Insights into peptidylarginine deiminase expression and citrullination pathways

Although PAD enzymes have high sequence homology, each enzyme isoform has its own features, including unique functions and specific tissue expression. PADs are expressed throughout the body but have a preference for structural proteins and nuclear substrates, such as histones. Therefore, the latest insights reveal how PAD activity affects cytoskeletal organization and gene expression. Evidence for extracellular citrullination is emerging in physiology and pathology. Recent insights in periodontitis show that exogenous proteins citrullinated by Porphyromonas gingivalis do not generate autoreactivity and dispute the role of P. gingivalis role in loss of tolerance. Aberrant citrullinated proteins disturb normal physiological processes in many inflammatory disorders and cancers outside rheumatoid arthritis or multiple sclerosis. Citrullinated histones in plasma are markers of bacterial and viral sepsis. Peptidylarginine deiminases (PADs) are calcium-dependent enzymes that mediate citrullination, an irreversible post-translational modification (PTM). PAD enzymes have received increasing attention in (patho-)physiology since multi-omics analysis accelerated their expression profiling. Here, we provide a comprehensive overview of PAD expression at the RNA and protein levels, and a list of annotated substrates per PAD isozyme. We discuss novel roles of citrullination in cellular growth, epigenetic regulation, tissue remodeling, inflammation, and cancer in mouse models and humans. Additionally, we cluster similar effects of protein deimination to offer a different perspective and improve our understanding of citrullination in health and disease. Citrullination should no longer be considered as a rare PTM, but as an important regulatory mechanism in physiology and pathology. Peptidylarginine deiminases (PADs) are calcium-dependent enzymes that mediate citrullination, an irreversible post-translational modification (PTM). PAD enzymes have received increasing attention in (patho-)physiology since multi-omics analysis accelerated their expression profiling. Here, we provide a comprehensive overview of PAD expression at the RNA and protein levels, and a list of annotated substrates per PAD isozyme. We discuss novel roles of citrullination in cellular growth, epigenetic regulation, tissue remodeling, inflammation, and cancer in mouse models and humans. Additionally, we cluster similar effects of protein deimination to offer a different perspective and improve our understanding of citrullination in health and disease. Citrullination should no longer be considered as a rare PTM, but as an important regulatory mechanism in physiology and pathology. uncontrolled citrullination when PADs are too active and modify too many arginine residues or citrullinate substrates that should remain unmodified. antibodies that recognize citrullinated proteins. ACPAs are typically generated during the autoimmune response observed in patients with RA. Therefore, ACPAs are currently used for the diagnosis of this disease. chemotactic cytokines that mediate the directional recruitment of immune cells through G-protein-coupled receptors. chemical inhibitor of PAD activity. reaction that converts a citrulline to an arginine amino acid. development of immune responses against epitopes that differ from the epitope that was recognized by T cell receptors or antibodies at the onset of a specific immune reaction. These new epitopes may be present on endogenous proteins instead of the disease-causing epitope and, therefore, sustain autoinflammation. in the cell cycle, cells grow in the G1 phase and transition to the S-phase, during which DNA is replicated. p53 controls this transition phase and interrupts cell cycles that contain damaged DNA. large molecules expressed by Gram-negative bacteria; comprise a lipid and a sugar chain and are considered endotoxins. foreign antigens that resemble self-antigens in their structure or sequence, making them more prone to break self-tolerance. form of cellular defence in which neutrophils expulse DNA to the extracellular environment to stimulate microbial clearance. complex of transcription factors that mediate the expression of proinflammatory genes, such as those encoding cytokines and chemokines. to distinguish between free amino acids and protein-bound amino acids, ‘peptidyl’ precedes the specific amino acid to indicate it is incorporated in a protein. single molecules or proteins that combine to form a complex with multiple entities. translated proteins can be modified chemically or enzymatically in a PTM that may change their biological function. propagation of action potentials along myelinated axons. genetic polymorphism that only affects a single nucleotide in the DNA sequence. blood-clotting process. class of receptors that are expressed by macrophages and dendritic cells that recognize microbial molecules, such as LPS.