{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPeptidylarginine deiminase 4 (PADI4) is a Ca²⁺‐dependent enzyme that catalyzes the conversion of arginine residues to citrulline, a posttranslational modification with profound immunological consequences. The generation of citrullinated proteins plays a pivotal role in rheumatoid arthritis (RA), as numerous genetic association studies have implicated PADI4 as a susceptibility locus. Specific haplotypes of the gene enhance transcript stability and are correlated with the production of autoantibodies against citrullinated peptides, thereby contributing to the breakdown of immune tolerance and the progression of joint inflammation and destruction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its autoimmune implications, PADI4 functions as a critical epigenetic regulator. By citrullinating arginine and monomethylated arginine residues on histone tails, it alters chromatin architecture and modulates the transcription of key genes—including those governed by the tumor suppressor p53. This activity interplays with other histone modifications such as methylation and acetylation, thereby influencing physiological processes ranging from cell cycle control to apoptosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and mechanistic studies have further illuminated PADI4’s multifaceted roles. Its three‐dimensional structure exhibits an elongated fold with multiple non–EF‐hand Ca²⁺–binding sites that, upon calcium binding, undergo conformational rearrangements essential for creating an active substrate–binding cleft. In neutrophils, PADI4–mediated histone citrullination is a key step in the formation of neutrophil extracellular traps (NETs), contributing to innate host defense and, paradoxically, to inflammatory tissue injury. Beyond these immunological functions, PADI4 citrullinates nonhistone proteins implicated in cancer and cell death pathways—altering protein stability, modulating apoptotic cascades, and influencing processes such as epithelial–mesenchymal transition. Genetic polymorphisms and autoantibody interactions with PADI4 further modulate its activity in diverse pathophysiological settings, ranging from defective microbial killing and excessive NET release to aberrant transcriptional regulation in inflammatory and neoplastic diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "42"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Akari Suzuki, Ryo Yamada, Xiaotian Chang, et al. 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