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

Area of Science:

• Cell Biology
• Molecular Biology
• Pharmacology

Background:

• Lysosomes are critical cellular organelles involved in degradation and signaling.
• Lysosome dysfunction is linked to numerous cellular processes and human diseases.
• Understanding cellular responses to lysosome damage is crucial for therapeutic development.

Purpose of the Study:

• To identify natural small-molecule compounds that induce lysosomal abnormality.
• To investigate the cellular effects and signaling pathways involved in ervachinine-induced lysosome damage.
• To explore the potential of lysosome-damaging compounds in disease research.

Main Methods:

• Screening of natural small-molecule compounds in Caenorhabditis elegans (C. elegans) model system.
• Identification and characterization of vobasinyl-ibogan type bisindole alkaloids (ervachinines A-D).
• Assessment of lysosomal enlargement, cell death pathways, and signaling mechanisms (STAT3, RIP1, RIP3) in C. elegans and mammalian cells.

Main Results:

• Ervinachinines A-D were identified as compounds causing lysosome enlargement in C. elegans.
• These compounds induced germ line cell death independently of canonical apoptosis.
• In mammalian cells, ervachinines A-D caused lysosomal damage, cathepsin leakage, inhibited autophagosome degradation, and led to necrotic cell death.
• Ervinachinine-induced lysosome damage and cell death were dependent on STAT3 signaling.

Conclusions:

• Ervinachinines A-D are potent inducers of lysosome damage and cell death.
• STAT3 signaling plays a key role in ervachinine-induced lysosomal cell death.
• Lysosome-damaging compounds like ervachinines are valuable tools for studying lysosome homeostasis and related human disorders.