Description
Protein arginine deiminase 4 (PAD4) catalyzes the conversion of arginine residues to citrulline within cellular protein substrates, resulting in the loss of a positive charge, which can alter protein structure and/or function. It is expressed in neutrophils, as well as a variety of tissues, including the brain, liver, lung, and kidney. PAD4 has a key role in NETosis, a lytic form of cell death characterized by the release of neutrophil extracellular traps (NETs). Upon neutrophil activation, PAD4 translocates to the nucleus where it citrullinates histones, initiating chromatin decondensation and the release of NETs. Neutrophils isolated from
Pad4-/- mice exhibit decreased citrullination of histone H3 under both basal and LPS-stimulated conditions and are defective for NET formation in response to stimulation with LPS, phorbol 12-myristate 13-acetate (PMA; ), or hydrogen peroxide.
Pad4-/- mice exhibit larger lesions than wild-type mice in a model of necrotizing fasciitis induced by M1 group A
S. pyogenes lacking the extracellular DNase Sda1.
Pad4-deficient mice also exhibit reduced infarct size in a model of myocardial ischemia-reperfusion injury and reduced tumor growth in a Lewis lung carcinoma model.
PADI4 SNPs, including G55S, V82A, and G112A, are associated with rheumatoid arthritis in humans. Cayman’s PAD4 (human, recombinant) protein contains the G55S, V82A, and G112A SNPs and can be used for enzyme activity assays.
References
[1] MéLANIE DEMERS. Priming of neutrophils toward NETosis promotes tumor growth.[J]. Oncoimmunology, 2016, 5 5: e1134073. DOI:
10.1080/2162402x.2015.1134073[2] JUSTIN E JONES. Protein arginine deiminase 4 (PAD4): Current understanding and future therapeutic potential.[J]. Current opinion in drug discovery & development, 2009, 12 5: 616-627.
[3] PINGXIN LI. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps.[J]. Journal of Experimental Medicine, 2010, 207 9: 1853-1862. DOI:
10.1084/jem.20100239[4] HAWA RACINE THIAM. NETosis proceeds by cytoskeleton and endomembrane disassembly and PAD4-mediated chromatin decondensation and nuclear envelope rupture.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2020: 7326-7337. DOI:
10.1073/pnas.1909546117[5] ALEXANDER S SAVCHENKO. VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice.[J]. Blood, 2014, 123 1: 141-148. DOI:
10.1182/blood-2013-07-514992[6] AKARI SUZUKI. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis[J]. Nature genetics, 2003, 34 4: 395-402. DOI:
10.1038/ng1206[7] MARíA TERESA MARTíN MONREAL. Applicability of Small-Molecule Inhibitors in the Study of Peptidyl Arginine Deiminase 2 (PAD2) and PAD4.[J]. Frontiers in Immunology, 2021: 716250. DOI:
10.3389/fimmu.2021.716250[8] TYRILLSHALL DAMIANA . Citrullination of fibrinogen by peptidylarginine deiminase 2 impairs fibrin clot structure[J]. Clinica Chimica Acta, 2020, 501: Pages 6-11. DOI:
10.1016/j.cca.2019.10.033[9] DRES DAMGAARD. Relative efficiencies of peptidylarginine deiminase 2 and 4 in generating target sites for anti-citrullinated protein antibodies in fibrinogen, alpha-enolase and histone H3.[J]. PLoS ONE, 2018: e0203214. DOI:
10.1371/journal.pone.0203214
