1.C. elegans-based screen identifies lysosome-damaging alkaloids that induce STAT3-dependent lysosomal cell death.
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
Protein & Cell 2018;9(12):1013-1026
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.
Alkaloids
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pharmacology
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Animals
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Caenorhabditis elegans
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cytology
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drug effects
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metabolism
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Cell Death
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drug effects
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Cell Survival
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drug effects
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HeLa Cells
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Humans
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Lysosomes
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drug effects
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pathology
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STAT3 Transcription Factor
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metabolism
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Signal Transduction
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drug effects
2.A pair of transporters controls mitochondrial Zn2+ levels to maintain mitochondrial homeostasis.
Tengfei MA ; Liyuan ZHAO ; Jie ZHANG ; Ruofeng TANG ; Xin WANG ; Nan LIU ; Qian ZHANG ; Fengyang WANG ; Meijiao LI ; Qian SHAN ; Yang YANG ; Qiuyuan YIN ; Limei YANG ; Qiwen GAN ; Chonglin YANG
Protein & Cell 2022;13(3):180-202
Zn2+ is required for the activity of many mitochondrial proteins, which regulate mitochondrial dynamics, apoptosis and mitophagy. However, it is not understood how the proper mitochondrial Zn2+ level is achieved to maintain mitochondrial homeostasis. Using Caenorhabditis elegans, we reveal here that a pair of mitochondrion-localized transporters controls the mitochondrial level of Zn2+. We demonstrate that SLC-30A9/ZnT9 is a mitochondrial Zn2+ exporter. Loss of SLC-30A9 leads to mitochondrial Zn2+ accumulation, which damages mitochondria, impairs animal development and shortens the life span. We further identify SLC-25A25/SCaMC-2 as an important regulator of mitochondrial Zn2+ import. Loss of SLC-25A25 suppresses the abnormal mitochondrial Zn2+ accumulation and defective mitochondrial structure and functions caused by loss of SLC-30A9. Moreover, we reveal that the endoplasmic reticulum contains the Zn2+ pool from which mitochondrial Zn2+ is imported. These findings establish the molecular basis for controlling the correct mitochondrial Zn2+ levels for normal mitochondrial structure and functions.
Animals
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Caenorhabditis elegans/metabolism*
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Cation Transport Proteins/genetics*
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Homeostasis
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Mitochondria/metabolism*
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Zinc/metabolism*