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

Autor: Li Y; 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.; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China. oceanyangli@fudan.edu.cn., Zhang Y; State Key Laboratory of Phytochemistry and Plant Resources in Western China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650021, China., Gan Q; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China., Xu M; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China., Ding X; State Key Laboratory of Phytochemistry and Plant Resources in Western China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650021, China., Tang G; State Key Laboratory of Phytochemistry and Plant Resources in Western China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650021, China., Liang J; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China., Liu K; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China., Liu X; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China., Wang X; 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., Guo L; State Key Laboratory of Phytochemistry and Plant Resources in Western China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650021, China., Gao Z; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China., Hao X; 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.; The Key Laboratory of Chemistry for Natural Product of Guizhou Province, Chinese Academy of Science, Guiyang, 550002, China. haoxj@mail.kib.ac.cn., Yang C; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China. clyang@genetics.ac.cn.; 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. clyang@genetics.ac.cn.
Jazyk: angličtina
Zdroj: Protein & cell [Protein Cell] 2018 Dec; Vol. 9 (12), pp. 1013-1026. Date of Electronic Publication: 2018 Apr 02.
DOI: 10.1007/s13238-018-0520-0
Abstrakt: 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.
Databáze: MEDLINE
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