Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.
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ABSTRACT:
SUBMITTER: Lewis HD
PROVIDER: S-EPMC4397581 | biostudies-literature | 2015 Mar
REPOSITORIES: biostudies-literature
Publications
Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.
Lewis Huw D HD Liddle John J Coote Jim E JE Atkinson Stephen J SJ Barker Michael D MD Bax Benjamin D BD Bicker Kevin L KL Bingham Ryan P RP Campbell Matthew M Chen Yu Hua YH Chung Chun-Wa CW Craggs Peter D PD Davis Rob P RP Eberhard Dirk D Joberty Gerard G Lind Kenneth E KE Locke Kelly K Maller Claire C Martinod Kimberly K Patten Chris C Polyakova Oxana O Rise Cecil E CE Rüdiger Martin M Sheppard Robert J RJ Slade Daniel J DJ Thomas Pamela P Thorpe Jim J Yao Gang G Drewes Gerard G Wagner Denisa D DD Thompson Paul R PR Prinjha Rab K RK Wilson David M DM
Nature chemical biology 20150126 3
PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored. ...[more]
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Project description:Peptidylarginine deiminases, or PADs, convert arginine residues to the non-ribosomally encoded amino acid citrulline in a variety of protein substrates. PAD4 is expressed in granulocytes and is essential for the formation of neutrophil extracellular traps (NETs) via PAD4-mediated histone citrullination. Citrullination of histones is thought to promote NET formation by inducing chromatin decondensation and facilitating the expulsion of chromosomal DNA that is coated with antimicrobial molecules. Numerous stimuli have been reported to lead to PAD4 activation and NET formation. However, how this signaling process proceeds and how PAD4 becomes activated in cells is largely unknown. Herein, we describe the various stimuli and signaling pathways that have been implicated in PAD4 activation and NET formation, including the role of reactive oxygen species generation. To provide a foundation for the above discussion, we first describe PAD4 structure and function, and how these studies led to the development of PAD-specific inhibitors. A comprehensive survey of the receptors and signaling pathways that regulate PAD4 activation will be important for our understanding of innate immunity, and the identification of signaling intermediates in PAD4 activation may also lead to the generation of pharmaceuticals to target NET-related pathogenesis.
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Project description:NET formation is a default epigenetic program controlled by PAD4 in apoptotic neutrophils
| PRJNA1008263 | ENA
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