Importantly, the molecular mechanisms involved in these effects are largely unknown, and here we perform the first genomic characterisation of the venom death pathway. The venoms of box jellyfish are mixtures of bioactive proteins that can cause potent haemolytic activity, cytotoxicity, membrane pore formation, inflammation, in vivo cardiovascular collapse and lethal effects in experimental animals 4, 5, 6. fleckeri envenoming can be life-threatening, however for the vast majority of cases patients suffer extreme pain and local tissue destruction 2, 3. Contact with jellyfish tentacles will trigger the explosive release of nematocysts that deliver potent and rapid-acting venom into the victim or prey. The box jellyfish, Chironex fleckeri, is one of the most venomous animal in the world 1. These results highlight the power of whole genome CRISPR screening to investigate venom mechanisms of action and to rapidly identify new medicines. We also discover a venom antidote that functions up to 15 minutes after exposure and suppresses tissue necrosis and pain in mice. Informatics analysis of host genes required for venom cytotoxicity reveal pathways not previously implicated in cell death. Targeting ATP2B1 prevents venom action and confers long lasting protection. We identify the peripheral membrane protein ATP2B1, a calcium transporting ATPase, as one host factor required for venom cytotoxicity. ![]() 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. Despite rapid and potent venom action, basic mechanistic insight is lacking. ![]() The box jellyfish Chironex fleckeri is extremely venomous, and envenoming causes tissue necrosis, extreme pain and death within minutes after severe exposure.
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