RESEARCH ARTICLE

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

  • Yang Li , 1,3 ,
  • Yu Zhang 2 ,
  • Qiwen Gan 3 ,
  • Meng Xu 3 ,
  • Xiao Ding 2 ,
  • Guihua Tang 2 ,
  • Jingjing Liang 3 ,
  • Kai Liu 3 ,
  • Xuezhao Liu 3 ,
  • Xin Wang 5 ,
  • Lingli Guo 2 ,
  • Zhiyang Gao 3 ,
  • Xiaojiang Hao , 2,4 ,
  • Chonglin Yang , 3,5
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  • 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

Received date: 23 Nov 2017

Accepted date: 16 Jan 2018

Published date: 19 Dec 2018

Copyright

2018 The Author(s) 2018. This article is an open access publication

Abstract

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 lysosomal 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.

Cite this article

Yang Li , Yu Zhang , Qiwen Gan , Meng Xu , Xiao Ding , Guihua Tang , Jingjing Liang , Kai Liu , Xuezhao Liu , Xin Wang , Lingli Guo , Zhiyang Gao , Xiaojiang Hao , Chonglin Yang . C. elegans-based screen identifies lysosome-damaging alkaloids that induce STAT3-dependent lysosomal cell death[J]. Protein & Cell, 2018 , 9(12) : 1013 -1026 . DOI: 10.1007/s13238-018-0520-0

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