Protein-arginine deiminase type-4 (PAD4) (PAD4)

Protein-arginine deiminase type-4 (PAD4) is a calcium-dependent enzyme that catalyzes the post-translational conversion of arginine residues in proteins to citrulline, a process known as citrullination or deimination [3, 4]. It is unique among the PAD family for its nuclear localization, where it modifies histones (H1, H3, and H4) to regulate gene expression and promote chromatin decondensation [2, 17]. PAD4 is a critical mediator of the innate immune response, specifically through its role in the formation of neutrophil extracellular traps (NETs), which are extracellular fibers of DNA and proteins that trap and kill pathogens [10, 13]. Dysregulation of PAD4 is strongly associated with the pathogenesis of rheumatoid arthritis (RA), as it generates citrullinated neoantigens that trigger the production of anti-citrullinated protein antibodies (ACPAs), a key diagnostic marker [1, 11]. Beyond RA, PAD4 is implicated in various cancers, where it acts as a transcriptional corepressor, and in other inflammatory and neurodegenerative conditions [7, 17]. Therapeutic development focuses on small-molecule inhibitors, such as GSK484 and JBI-589, which aim to block enzymatic activity to alleviate inflammation and prevent NET-mediated tissue damage [12, 15].

Other names

PADI4Peptidylarginine deiminase IVPeptidylarginine deiminase type IVHL-60 PADPADI5PDI4PDI5

Inhibition of enzymatic activity (citrullination), prevention of histone modification, and suppression of neutrophil extracellular trap (NET) formation.