Department of Pharmacology, Key Laboratory of Metabolism and Molecular Medicine (The Ministry of Education), School of Basic Medical Science, Fudan University, Shanghai, 200032, China.
State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
Protein Cell. 2018 Dec;9(12):1013-1026. doi: 10.1007/s13238-018-0520-0. Epub 2018 Apr 2.
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.
溶酶体是细胞内的降解和信号中心，其功能障碍会损害多种细胞过程。为了了解溶酶体损伤的细胞效应，我们使用秀丽隐杆线虫（C. elegans）作为模型系统，筛选了诱导溶酶体异常的天然小分子化合物。鉴定出了一组伏巴因-异波林型双吲哚生物碱（ervachinines A-D），它们在 C. elegans 巨噬样细胞中引起溶酶体增大。有趣的是，这些化合物独立于经典的细胞凋亡途径在生殖系中引发细胞死亡。在哺乳动物细胞中，ervachinines A-D 诱导溶酶体增大和损伤，导致组织蛋白酶蛋白酶的漏出、自噬体降解的抑制和坏死性细胞死亡。进一步的分析表明，ervachinine 诱导的溶酶体损伤和溶酶体细胞死亡依赖于 STAT3 信号，但不依赖于 RIP1 或 RIP3 信号。这些发现表明，溶酶体损伤化合物是解析溶酶体动态平衡和与溶酶体相关的人类疾病信号机制的有前途的试剂。
