Abstract
BackgroundCystic 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. MethodsFull-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. ResultsFull-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. ConclusionsCitrullination 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.
Highlights
Cystic fibrosis (CF) is the most common genetic disease with Mendelian inheritance in Caucasians, affecting approximately 3 million individuals worldwide [1]
A strong bactericidal effect was seen in the presence of sodium chloride, indicating that extracellular histones may play a role as innate antibiotics in the airways during inflammation
Eight overlapping 20 amino acid peptides encompassing the length of histone H3.1 were used to investigate growth inhibition of P. aeruginosa using a radial diffusion assay (Fig. 1C)
Summary
Cystic fibrosis (CF) is the most common genetic disease with Mendelian inheritance in Caucasians, affecting approximately 3 million individuals worldwide [1]. The four core histones share a common trait, possessing tail regions upon which PTMs may occur [8]. One such modification is citrullination, whereby the amino acid peptidyl-arginine is replaced by peptidylcitrulline. This is catalyzed by deiminases of which there are five types: PADI 1, 2, 3, 4, and 6. Neutrophils have a high content of PADI4, a deiminase which is important for the formation of NETs [9]. 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
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