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

被引:14
作者
Li, Yang [1 ,3 ]
Zhang, Yu [2 ]
Gan, Qiwen [3 ]
Xu, Meng [3 ]
Ding, Xiao [2 ]
Tang, Guihua [2 ]
Liang, Jingjing [3 ]
Liu, Kai [3 ]
Liu, Xuezhao [3 ]
Wang, Xin [5 ]
Guo, Lingli [2 ]
Gao, Zhiyang [3 ]
Hao, Xiaojiang [2 ,4 ]
Yang, Chonglin [3 ,5 ]
机构
[1] Fudan Univ, Sch Basic Med Sci, Minist Educ, Dept Pharmacol,Key Lab Metab & Mol Med, Shanghai 200032, Peoples R China
[2] Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources Western, Kunming 650021, Yunnan, Peoples R China
[3] Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Mol Dev Biol, Beijing 100101, Peoples R China
[4] Chinese Acad Sci, Key Lab Chem Nat Prod Guizhou Prov, Guiyang 550002, Guizhou, Peoples R China
[5] Yunnan Univ, Sch Life Sci, Ctr Life Sci, State Key Lab Conservat & Utilizat Bioresources Y, Kunming 650091, Yunnan, Peoples R China
基金
中国国家自然科学基金;
关键词
lysosome; alkaloids; lysosomal cell death; STAT3; Caenorhabditis elegans; MEMBRANE PERMEABILIZATION; AUTOPHAGY; BIOGENESIS; APOPTOSIS; DISRUPTION;
D O I
10.1007/s13238-018-0520-0
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
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 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.
引用
收藏
页码:1013 / 1026
页数:14
相关论文
共 30 条
  • [1] Lipotoxicity-mediated cell dysfunction and death involve lysosomal membrane permeabilization and cathepsin L activity
    Almaguel, Frankis G.
    Liu, Jo-Wen
    Pacheco, Fabio J.
    De Leon, Daisy
    Casiano, Carlos A.
    De Leon, Marino
    [J]. BRAIN RESEARCH, 2010, 1318 : 133 - 143
  • [2] Lysosomal membrane permeabilization in cell death
    Boya, P.
    Kroemer, G.
    [J]. ONCOGENE, 2008, 27 (50) : 6434 - 6451
  • [3] Probing the cathepsin D using a BODIPY EL-pepstatin A: applications in fluorescence polarization and microscopy
    Chen, CS
    Chen, WNU
    Zhou, MJ
    Arttamangkul, S
    Haugland, RP
    [J]. JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS, 2000, 42 (03): : 137 - 151
  • [4] Fares H, 2001, GENETICS, V159, P133
  • [5] Preoperative chemoradiotherapy with cisplatin and docetaxel for stage IIIB non-small-cell lung cancer: 10-year follow-up of the SAKK 16/01 trial
    Fruh, M.
    Ris, H. B.
    Xyrafas, A.
    Peters, S.
    Mirimanoff, R. O.
    Gautschi, O.
    Pless, M.
    Stupp, R.
    [J]. ANNALS OF ONCOLOGY, 2016, 27 (10) : 1971 - 1972
  • [6] Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process
    Gonzalez, P.
    Mader, I.
    Tchoghandjian, A.
    Enzenmueller, S.
    Cristofanon, S.
    Basit, F.
    Debatin, K-M
    Fulda, S.
    [J]. CELL DEATH AND DIFFERENTIATION, 2012, 19 (08) : 1337 - 1346
  • [7] Indole alkaloids from Ervatamia chinensis
    Guo, Ling-Li
    He, Hong-Ping
    Di, Ying-Tong
    Li, Shi-Fei
    Cheng, Yuan-Yuan
    Yang, Wei
    Li, Yan
    Yu, Jian-Ping
    Zhang, Yu
    Hao, Xiao-Jiang
    [J]. PHYTOCHEMISTRY, 2012, 74 : 140 - 145
  • [8] THE GENETICS OF PROGRAMMED CELL-DEATH IN THE NEMATODE CAENORHABDITIS-ELEGANS
    HORVITZ, HR
    SHAHAM, S
    HENGARTNER, MO
    [J]. COLD SPRING HARBOR SYMPOSIA ON QUANTITATIVE BIOLOGY, 1994, 59 : 377 - 385
  • [9] Stat3 controls lysosomal-mediated cell death in vivo
    Kreuzaler, Peter A.
    Staniszewska, Anna D.
    Li, Wenjing
    Omidvar, Nader
    Kedjouar, Blandine
    Turkson, James
    Poli, Valeria
    Flavell, Richard A.
    Clarkson, Richard W. E.
    Watson, Christine J.
    [J]. NATURE CELL BIOLOGY, 2011, 13 (03) : 303 - U263
  • [10] Protein kinase C controls lysosome biogenesis independently of mTORC1
    Li, Yang
    Xu, Meng
    Ding, Xiao
    Yan, Chen
    Song, Zhiqin
    Chen, Lianwan
    Huang, Xiahe
    Wang, Xin
    Jian, Youli
    Tang, Guihua
    Tang, Changyong
    Di, Yingtong
    Mu, Shuzhen
    Liu, Xuezhao
    Liu, Kai
    Li, Ting
    Wang, Yingchun
    Miao, Long
    Guo, Weixiang
    Hao, Xiaojiang
    Yang, Chonglin
    [J]. NATURE CELL BIOLOGY, 2016, 18 (10) : 1065 - 1077