C. elegans-based screen identifies lysosome-damaging alkaloids that induce STAT3-dependent lysosomal cell death.
10.1007/s13238-018-0520-0
- Author:
Yang LI
1
;
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
4
;
Lingli GUO
2
;
Zhiyang GAO
3
;
Xiaojiang HAO
5
;
Chonglin YANG
6
Author Information
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. oceanyangli@fudan.edu.cn.
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. 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.
5. State Key Laboratory of Phytochemistry and Plant Resources in Western China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650021, China. haoxj@mail.kib.ac.cn.
6. State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China. clyang@genetics.ac.cn.
- Publication Type:Journal Article
- Keywords:
Caenorhabditis elegans;
STAT3;
alkaloids;
lysosomal cell death;
lysosome
- MeSH:
Alkaloids;
pharmacology;
Animals;
Caenorhabditis elegans;
cytology;
drug effects;
metabolism;
Cell Death;
drug effects;
Cell Survival;
drug effects;
HeLa Cells;
Humans;
Lysosomes;
drug effects;
pathology;
STAT3 Transcription Factor;
metabolism;
Signal Transduction;
drug effects
- From:
Protein & Cell
2018;9(12):1013-1026
- CountryChina
- Language:English
-
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 small-molecule 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 lysosome-damaging compounds are promising reagents for dissecting signaling mechanisms underlying lysosome homeostasis and lysosome-related human disorders.
