Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation

By Yanming Wang, Ming-Ming Li, Sonja C. Stadler, Sarah Correll, Pingxin Li, Danchen Wang, R. Hayama, L. Leonelli, Hyunsil Han, S. Grigoryev and 2 more. Journal of Cell Biology, 2009

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Peripheral blood neutrophils form highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs), that have been implicated in innate immune response to bacterial infection. Neutrophils express high levels of peptidylarginine deiminase 4 (PAD4), which catalyzes histone citrullination. However, whether PAD4 or histone citrullination plays a role in chromatin structure in neutrophils is unclear. In this study, we show that the hypercitrullination of histones by PAD4 mediates chromatin decondensation. Histone hypercitrullination is detected on highly decondensed chromatin in HL-60 granulocytes and blood neutrophils. The inhibition of PAD4 decreases histone hypercitrullination and the formation of NET-like structures, whereas PAD4 treatment of HL-60 cells facilitates these processes. The loss of heterochromatin and multilobular nuclear structures is detected in HL-60 granulocytes after PAD4 activation. Importantly, citrullination of biochemically defined avian nucleosome arrays inhibits their compaction by the linker histone H5 to form higher order chromatin structures. Together, these results suggest that histone hypercitrullination has important functions in chromatin decondensation in granulocytes/neutrophils.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/e19ceed0448266895ff4d5a31247beb2f47f7a76

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Citations in the corpus

Thrombosis: tangled up in NETs. (2014, background): “It is now known that the nuclear swelling is due to chromatin decondensation driven by peptidylarginine deiminase 4 (PAD4).(12) PAD4 is a protein citrullinating enzyme that enters the nucleus to modify histones.”
Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 (2011, background): “Thus, genetic inhibition of the major histone-citrullinating enzyme, that is, peptidylarginine deiminase 4 (PAD4), interfered with NET release by HL-60 cells stimulated with Ca2þ ionophores or Shigella flexneri.(164) Importantly, cell death with netotic features has been observed in a subset of cyto”
Neutrophil extracellular traps: Is immunity the second function of chromatin? (2012, background): “In NETs and decondensed nuclei, but not in the nucleus of unstimulated neutrophils, his tones are citrullinated (Neeli et al., 2008, 2009; Wang et al., 2009).”
The neutrophil in vascular inflammation (2011, background): “In addition to their direct antimicrobial effects, there is also evidence that histones may have a regulatory role during NET formation, as the process of NET formation starts with histone hypercitrullination and decondensation of the associated nuclear chromati”
The Multifaceted Functions of Neutrophils (2013, background): “Deimination of histones (mainly conversion of arginine side chains to citrullines) is thought to be required for disassembly of chromatin to allow full NET dispersion (122).”
PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps (2010, background): “We and others have recently found that an increase in histone citrullination is associated with chromatin decondensation during NET formation (Neeli et al., 2008; Wang et al., 2009).”
Pollutants inducing epigenetic changes and diseases (2019, background): “2011; Lakatos and Jobst 1989), citrullination (Thompson and Fast 2006; Wang et al. 2009), sumoylation (Nathan et al.”
Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones (2012, background): “with DNA and other proteins or histone degradation during NET formation or the protein complexes in NET could be responsible for such differences [7,59,62].”
NETosis: how vital is it? (2013, background): “Wang et al found that histones modified by citrullination were required for NETosis and that inhibition of PAD4, the enzyme required for citrullinating proteins in neutrophils, disabled NET formation.(22) Mice with PAD4 deficiency displayed impaired NETosis and were highly susceptible to some severe”
Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury (2015, background): “In addition to ROS, several other pathways have been reported to be involved in NET formation, such as peptidyl arginine deiminase (PAD) 4 [64], the Raf-MEK (mitogen-activated kinase/ERK kinase)-ERK (extracellular signalregulated kinase) pathway [65] and autophagy [66].”