论文标题： Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote

期刊：Nature Communications

作者：Man-Tat Lau, John Manion, Jamie B. Littleboy, Lisa Oyston, Thang M. Khuong, Qiao-Ping Wang, David T. Nguyen, Daniel Hesselson, Jamie E. Seymour, G. Gregory Neely

发表时间：2019/04/30

数字识别码：10.1038/s41467-019-09681-1

原文链接：http://t.cn/EoTWFyn

微信链接：https://mp.weixin.qq.com/s/f5pQpML_Tm7jsliHpOH9Iw

《自然-通讯》本周发表的一篇论文 Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote 报道了一种箱形水母（Chironex fleckeri）毒液的解毒剂，可以抑制小鼠的组织死亡和疼痛。研究表明，相同技术或能用于对抗其它动物的毒素。

图1: 澳大利亚的箱形水母是世界上毒性最强的动物之一 图源：Jamie Seymour

箱形水母是世界上毒性最强的动物之一，其毒液会引起极度疼痛，在严重暴露后几分钟内便可致死。然而，这种速发性毒素作用的机制尚不清楚。目前的治疗手段效果有限，且都无法直接作用于毒液暴露的最常见临床表现——疼痛或局部组织死亡。在分子水平上对毒性作用的认识不足是新疗法开发的一个主要障碍。

图2：箱型水母毒液多会引起坏死性细胞死亡。图源：Lau等

澳大利亚悉尼大学的Greg Neely和同事运用全基因组CRISPR筛选技术，对C. fleckeri毒液暴露后宿主细胞死亡所必需的基因进行了鉴定。作者识别出了毒液细胞毒性的数个必需基因，包括参与胆固醇生物合成的基因，并证明干涉这些基因可以提高对箱形水母毒素的抗性。此外，在毒液暴露后最多15分钟内给予小鼠2-羟丙基-β-环糊精可以缓解疼痛并抑制组织死亡——已知2-羟丙基-β-环糊精可以调节胆固醇，并能用于人体治疗尼曼-匹克病。

作者认为通过揭示毒液暴露后的细胞通路，研究结果能为其它水母毒液解毒剂的设计提供相关信息。

摘要：The box jellyfish Chironex fleckeri is extremely venomous, and envenoming causes tissue necrosis, extreme pain and death within minutes after severe exposure. Despite rapid and potent venom action, basic mechanistic insight is lacking. Here we perform molecular dissection of a jellyfish venom-induced cell death pathway by screening for host components required for venom exposure-induced cell death using genome-scale lenti-CRISPR mutagenesis. We identify the peripheral membrane protein ATP2B1, a calcium transporting ATPase, as one host factor required for venom cytotoxicity. Targeting ATP2B1 prevents venom action and confers long lasting protection. Informatics analysis of host genes required for venom cytotoxicity reveal pathways not previously implicated in cell death. We also discover a venom antidote that functions up to 15 minutes after exposure and suppresses tissue necrosis and pain in mice. These results highlight the power of whole genome CRISPR screening to investigate venom mechanisms of action and to rapidly identify new medicines.

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期刊介绍：Nature Communications (https://www.nature.com/ncomms/) is an open access journal that publishes high-quality research from all areas of the natural sciences. Papers published by the journal represent important advances of significance to specialists within each field.

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（来源：科学网）