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Citrullination of extracellular histone H3.1 reduces antibacterial activity and exacerbates its proteolytic degradation

Tanner, Lloyd LU ; Bhongir, Ravi K V LU ; Karlsson, Christofer A Q LU ; Le, Sandy ; Ljungberg, Johanna K LU ; Andersson, Pia LU ; Andersson, Cecilia LU ; Malmström, Johan LU ; Egesten, Arne LU and Single, Andrew B LU (2021) In Journal of Cystic Fibrosis 20(2). p.346-355
Abstract

BACKGROUND: Cystic fibrosis (CF), involves excessive airway accumulation of neutrophils, often in parallel with severe infection caused by Pseudomonas aeruginosa. Free histones are known to possess bactericidal properties, but the degree of antibacterial activity exerted on specific lung-based pathogens is largely unknown. Neutrophils have a high content of peptidyl deiminase 4 (PADI4), which citrullinate cationic peptidyl-arginines. In histone H3.1, several positions in the NH2-terminal tail are subject to citrullination.

METHODS: Full-length and segmented histone subunit H3.1 was investigated for bactericidal activity towards P. aeruginosa (strain PAO1). PADI4-induced citrullination of histone H3.1 was assessed for antibacterial... (More)

BACKGROUND: Cystic fibrosis (CF), involves excessive airway accumulation of neutrophils, often in parallel with severe infection caused by Pseudomonas aeruginosa. Free histones are known to possess bactericidal properties, but the degree of antibacterial activity exerted on specific lung-based pathogens is largely unknown. Neutrophils have a high content of peptidyl deiminase 4 (PADI4), which citrullinate cationic peptidyl-arginines. In histone H3.1, several positions in the NH2-terminal tail are subject to citrullination.

METHODS: Full-length and segmented histone subunit H3.1 was investigated for bactericidal activity towards P. aeruginosa (strain PAO1). PADI4-induced citrullination of histone H3.1 was assessed for antibacterial activity towards P. aeruginosa. Next, the effect of neutrophil elastase (NE)-mediated proteolysis of histone H3.1 was investigated. Finally, PADI4, H3.1, and citrullinated H3.1 were examined in healthy control and CF patient lung tissues.

RESULTS: Full-length histone H3.1 and sections of the histone H3.1 tail, displayed bactericidal activity towards P. aeruginosa. These antibacterial effects were reduced following citrullination by PADI4 or proteolysis by NE. Interestingly, citrullination of histone H3.1 exacerbated NE-mediated degradation. In CF lung tissue, citrullinated histone H3.1 and PADI4 immunoreactivity was abundant. Degraded histone H3.1 was detected in the sputum of CF patients but was absent in the sputum of healthy controls.

CONCLUSIONS: Citrullination impairs the antibacterial activity of histone H3.1 and exacerbates its proteolytic degradation by NE. Citrullination is likely to play an important role during resolution of acute inflammation. However, in chronic inflammation akin to CF, citrullination may dampen host defense and promote pathogen survival, as exemplified by P. aeruginosa.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Cystic Fibrosis
volume
20
issue
2
pages
346 - 355
publisher
Elsevier
external identifiers
  • pmid:32727663
  • scopus:85088793322
ISSN
1873-5010
DOI
10.1016/j.jcf.2020.07.010
language
English
LU publication?
yes
additional info
Copyright © 2020. Published by Elsevier B.V.
id
3bb55e1f-e27c-4561-9750-b7259411990d
date added to LUP
2020-07-31 19:47:12
date last changed
2021-06-08 04:19:08
@article{3bb55e1f-e27c-4561-9750-b7259411990d,
  abstract     = {<p>BACKGROUND: Cystic fibrosis (CF), involves excessive airway accumulation of neutrophils, often in parallel with severe infection caused by Pseudomonas aeruginosa. Free histones are known to possess bactericidal properties, but the degree of antibacterial activity exerted on specific lung-based pathogens is largely unknown. Neutrophils have a high content of peptidyl deiminase 4 (PADI4), which citrullinate cationic peptidyl-arginines. In histone H3.1, several positions in the NH2-terminal tail are subject to citrullination.</p><p>METHODS: Full-length and segmented histone subunit H3.1 was investigated for bactericidal activity towards P. aeruginosa (strain PAO1). PADI4-induced citrullination of histone H3.1 was assessed for antibacterial activity towards P. aeruginosa. Next, the effect of neutrophil elastase (NE)-mediated proteolysis of histone H3.1 was investigated. Finally, PADI4, H3.1, and citrullinated H3.1 were examined in healthy control and CF patient lung tissues.</p><p>RESULTS: Full-length histone H3.1 and sections of the histone H3.1 tail, displayed bactericidal activity towards P. aeruginosa. These antibacterial effects were reduced following citrullination by PADI4 or proteolysis by NE. Interestingly, citrullination of histone H3.1 exacerbated NE-mediated degradation. In CF lung tissue, citrullinated histone H3.1 and PADI4 immunoreactivity was abundant. Degraded histone H3.1 was detected in the sputum of CF patients but was absent in the sputum of healthy controls.</p><p>CONCLUSIONS: Citrullination impairs the antibacterial activity of histone H3.1 and exacerbates its proteolytic degradation by NE. Citrullination is likely to play an important role during resolution of acute inflammation. However, in chronic inflammation akin to CF, citrullination may dampen host defense and promote pathogen survival, as exemplified by P. aeruginosa.</p>},
  author       = {Tanner, Lloyd and Bhongir, Ravi K V and Karlsson, Christofer A Q and Le, Sandy and Ljungberg, Johanna K and Andersson, Pia and Andersson, Cecilia and Malmström, Johan and Egesten, Arne and Single, Andrew B},
  issn         = {1873-5010},
  language     = {eng},
  number       = {2},
  pages        = {346--355},
  publisher    = {Elsevier},
  series       = {Journal of Cystic Fibrosis},
  title        = {Citrullination of extracellular histone H3.1 reduces antibacterial activity and exacerbates its proteolytic degradation},
  url          = {http://dx.doi.org/10.1016/j.jcf.2020.07.010},
  doi          = {10.1016/j.jcf.2020.07.010},
  volume       = {20},
  year         = {2021},
}