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Citrullination of extracellular histone H3.1 reduces antibacterial activity and exacerbates its proteolytic degradation
Journal of Cystic Fibrosis ( IF 5.2 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.jcf.2020.07.010
Lloyd Tanner 1 , Ravi K V Bhongir 1 , Christofer A Q Karlsson 2 , Sandy Le 1 , Johanna K Ljungberg 1 , Pia Andersson 1 , Cecilia Andersson 3 , Johan Malmström 2 , Arne Egesten 1 , Andrew B Single 1
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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.

中文翻译:

胞外组蛋白 H3.1 的瓜氨酸化会降低抗菌活性并加剧其蛋白水解降解

背景技术囊性纤维化(CF)涉及中性粒细胞的过度气道积聚,通常与铜绿假单胞菌引起的严重感染同时发生。已知游离组蛋白具有杀菌特性,但对特定的基于肺的病原体的抗菌活性程度在很大程度上是未知的。中性粒细胞具有高含量的肽基脱亚胺酶 4 (PADI4),可瓜氨酸化阳离子肽基-精氨酸。在组蛋白 H3.1 中,NH2 末端尾部的几个位置受到瓜氨酸化的影响。方法研究全长和分段组蛋白亚基H3.1对铜绿假单胞菌(菌株PAO1)的杀菌活性。评估了 PADI4 诱导的组蛋白 H3.1 瓜氨酸化对铜绿假单胞菌的抗菌活性。接下来,中性粒细胞弹性蛋白酶 (NE) 介导的组蛋白 H3 蛋白水解的作用。1 进行了调查。最后,在健康对照和 CF 患者肺组织中检查 PADI4、H3.1 和瓜氨酸化 H3.1。结果 全长组蛋白 H3.1 和组蛋白 H3.1 尾部切片显示出对铜绿假单胞菌的杀菌活性。在 PADI4 瓜氨酸化或 NE 蛋白水解后,这些抗菌作用降低。有趣的是,组蛋白 H3.1 的瓜氨酸化加剧了 NE 介导的降解。在 CF 肺组织中,瓜氨酸组蛋白 H3.1 和 PADI4 免疫反应性丰富。在 CF 患者的痰液中检测到降解的组蛋白 H3.1,但在健康对照的痰液中不存在。结论瓜氨酸化损害组蛋白 H3.1 的抗菌活性并加剧其被 NE 蛋白水解降解。瓜氨酸化可能在急性炎症消退过程中发挥重要作用。
更新日期:2020-07-01
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