Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5.
Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5.
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DOI：
10.1126/sciadv.1700898
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发表时间：
2017-08
期刊：
影响因子：
13.6
通讯作者：
May RC
中科院分区：
文献类型：
--
作者：
Gilbert AS;Seoane PI;Sephton-Clark P;Bojarczuk A;Hotham R;Giurisato E;Sarhan AR;Hillen A;Velde GV;Gray NS;Alessi DR;Cunningham DL;Tournier C;Johnston SA;May RC
ERK5调节活病原体从吞噬细胞的非溶解性排出，以限制感染的传播。巨噬细胞吞噬，或非溶解性挤压，是一个知之甚少的过程，巨噬细胞释放活的病原体，他们未能杀死回细胞外环境。呕吐细胞病在脊椎动物中是保守的，并且发生在多种病原体中，但迄今为止，支持驱逐的宿主信号事件仍然完全未知。我们使用靶向抑制剂筛选确定MAP激酶ERK5作为呕吐细胞病的关键抑制因子。ERK5活性的药理抑制或基因操作显著提高人巨噬细胞的呕吐率，而ERK5信号通路的刺激抑制呕吐。最后，利用斑马鱼隐球菌病模型，我们发现体内ERK5活性降低会刺激呕吐细胞，并导致感染传播减少。因此，ERK5代表了第一个被确定的呕吐细胞病宿主信号调节因子，也是未来发展呕吐细胞调节疗法的潜在靶点。
ERK5 regulates nonlytic expulsion of live pathogens from phagocytes to limit dissemination of infections. Vomocytosis, or nonlytic extrusion, is a poorly understood process through which macrophages release live pathogens that they have failed to kill back into the extracellular environment. Vomocytosis is conserved across vertebrates and occurs with a diverse range of pathogens, but to date, the host signaling events that underpin expulsion remain entirely unknown. We use a targeted inhibitor screen to identify the MAP kinase ERK5 as a critical suppressor of vomocytosis. Pharmacological inhibition or genetic manipulation of ERK5 activity significantly raises vomocytosis rates in human macrophages, whereas stimulation of the ERK5 signaling pathway inhibits vomocytosis. Lastly, using a zebrafish model of cryptococcal disease, we show that reducing ERK5 activity in vivo stimulates vomocytosis and results in reduced dissemination of infection. ERK5 therefore represents the first host signaling regulator of vomocytosis to be identified and a potential target for the future development of vomocytosis-modulating therapies.
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DOI：
10.1083/jcb.201009119
发表时间：
2011-05-30
期刊：
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影响因子：
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