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.
Highlights
Lysosomes are acidic single-membrane organelles that function as the major sites for digesting cargoes received from several pathways, including endocytosis, phagocytosis and autophagy
These findings suggest that ervachinines A–D are promising candidates for dissecting the signals underlying lysosome homeostasis and for developing therapeutic reagents for human disorders resulting from defective apoptosis
C. elegans has 6 specialized macrophage-like cells, namely coelomocytes, which are highly active in fluid-phase endocytosis (Sato et al, 2016)
Summary
Lysosomes are acidic single-membrane organelles that function as the major sites for digesting cargoes received from several pathways, including endocytosis, phagocytosis and autophagy. The lysosome contains >60 different hydrolytic enzymes, many of which are activated at low pH. The acidity of the lysosomal lumen is generated and maintained by v-ATPase, an ATP-dependent proton pump. The lysosome contains over 150 membrane proteins that are required for the integrity and homeostasis of the organelle (Saftig and Klumperman, 2009). Impairment of lysosomal function is responsible for more than 70 lysosomal storage diseases (LSDs) (Macauley, 2016) and contributes to many other human diseases, such as neurodegenerative disorders and cancers (Nixon, 2013; Perera et al, 2015).
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