RRC ID 56192
著者 Li Y, Zhang Y, Gan Q, Xu M, Ding X, Tang G, Liang J, Liu K, Liu X, Wang X, Guo L, Gao Z, Hao X, Yang C.
タイトル C. elegans-based screen identifies lysosome-damaging alkaloids that induce STAT3-dependent lysosomal cell death.
ジャーナル Protein Cell
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.
巻・号 9(12)
ページ 1013-1026
公開日 2018-12-1
DOI 10.1007/s13238-018-0520-0
PII 10.1007/s13238-018-0520-0
PMID 29611115
PMC PMC6251801
MeSH Alkaloids / pharmacology* Animals Caenorhabditis elegans / cytology Caenorhabditis elegans / drug effects* Caenorhabditis elegans / metabolism Cell Death / drug effects* Cell Survival / drug effects HeLa Cells Humans Lysosomes / drug effects* Lysosomes / pathology STAT3 Transcription Factor / metabolism* Signal Transduction / drug effects
IF 7.575
引用数 7
リソース情報
線虫 tm1125 tm2388