C.elegans-based screen identifies lysosome-damaging alkaloids that induce STAT3-dependent lysosomal cell death

查看全文 作　　者：Yang [1,3]Li;Yu [2]Zhang;Qiwen [3]Gan;Meng [3]Xu;Xiao [2]Ding;Guihua [2]Tang;Jingjing [3]Liang;Kai [3]Liu;Xuezhao [3]Liu;Xin [5]Wang;Lingli [2]Guo;Zhiyang [3]Gao;Xiaojiang [2,4]Hao;Chonglin [3,5]Yang

机构地区：[1]Department of Pharmacology,Key Laboratory of Metabolism and Molecular Medicine (The Ministry of Education),School of Basic Medical Science,Fudan University,Shanghai 200032,China;[2]State Key Laboratory of Phytochemistry and Plant Resources in Western China,Kunming Institute of Botany,Chinese Academy of Sciences,Kunming 650021,China;[3]State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology,Chinese Academy of Sciences,Beijing 100101,China;[4]The Key Laboratory of Chemistry for Natural Product of Guizhou Province,Chinese Academy of Science,Guiyang 550002,China;[5]State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan,Center for Life Sciences,School of Life Sciences,Yunnan University,Kunming 650091,China

出　　处：《Protein & Cell》索引2018年第9卷第12期,共14页

基　　金：grants 31230043(to C.Yang); 21432010(to X.Hao and C.Yang); 81473122(to Y.Zhang)from the National Natural Science Foundation of China,2013CB910102 from the National Basic Research Program of China;the CAS Interdisciplinary Innovation Team (to C.Yang);the Youth Innovation Promotion Association of CAS (2015323). 摘　　要：Lysosomes are degradation and signaling centers within the cell,and their dysfunction impairs a wide variety of cellular processes.To understand the cellular effect of lysosome damage,we screened natural smallmolecule compounds that induce iysosomal abnormality using Caenorhabditis elegans (C.elegans)as a model system.A group of vobasinyl-ibogan type bisindole alkaloids (ervachinines A-D)were identified that caused lysosome enlargement in C.elegans macrophage-like cells.Intriguingly,these compounds triggered cell death in the germ line independently of the canonical apoptosis pathway.In mammalian cells, ervachinines A-D induced lysosomal enlargement and damage,leading to leakage of cathepsin proteases, inhibition of autophagosome degradation and necrotic cell death.Further analysis revealed that this ervachinine-induced lysosome damage and lysosomal cell death depended on STAT3 signaling,but not RIP1 or RIP3 signaling.These findings suggest that lysosomedamaging compounds are promising reagents for dissecting signaling mechanisms underlying lysosome homeostasis and lysosome-related human disorders. 关键词：LYSOSOME ALKALOIDS LYSOSOMAL cell death STAT3 CAENORHABDITIS elegans

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C.elegans-based screen identifies lysosome-damaging alkaloids that induce STAT3-dependent lysosomal cell death

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