V-ATPase V0 subunit activation mediates maduramicin-induced methuosis through blocking endolysosomal trafficking in vitro and in vivo

Zheng, Yuling; Xiao, Jing; Wang, Junqi; Dong, Bo; Guo, Dawei; Jiang, Hui; Sun, Haifeng; Lin, Peng; Jiang, Shanxiang; Gao, Xiaona

doi:10.1016/j.fct.2023.113922

Food and Chemical Toxicology

2023

DOI: 10.1016/j.fct.2023.113922

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V-ATPase V0 subunit activation mediates maduramicin-induced methuosis through blocking endolysosomal trafficking in vitro and in vivo

Yuling Zheng

Jing Xiao

Junqi Wang

et al.

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Cited by 2 publications

References 48 publications

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Kinase inhibitor-induced cell-type specific vacuole formation in the absence of canonical ATG5-dependent autophagy

Jose,

Sharma,

Insan

et al. 2023

Preprint

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Pyridinyl imidazole class p38 MAPKα/β (MAPK14/MAPK11) inhibitors including SB202190 have been shown to induce a cell-type specific defective autophagy response resulting in micron-scale vacuole formation and autophagy-dependent death. We had earlier shown that this is an off-target effect of SB202190. Here we provide evidence that the cell-type specific vacuole formation is independent of canonical autophagy pathway. While SB202190 seems to interfere with autophagic flux in many cell lines parallel to vacuolation, autophagy-deficient DU-145 cells and CRISPR/Cas9 gene-editedATG5knockout A549 cells also undergo vacuolation upon SB202190 treatment. Further analyses identified the late-endosomal GTPase RAB7 as a marker for the SB202190-induced micron-scale vacuoles. A screen for modulators of SB202190-induced vacuolation revealed molecules including multi-kinase inhibitor Sorafenib as inhibitor of vacuolation. Moreover VE-821, an ATR kinase inhibitor was found to phenocopy the cell-type specific vacuolation response of SB202190. To identify the factors determining the cell-type specificity of the vacuolation response induced by SB-compounds and VE-821, we compared the transcriptomics data from vacuole forming and non-vacuole forming cancer cell lines and identified a gene expression signature which may define sensitivity of cancer cells to these small-molecule kinase inhibitors. Further analyses using the small molecule tools and the gene signature discovered here, could reveal novel mechanisms regulating this interesting phenotype relevant to anti-cancer therapy.

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Kinase inhibitor-induced cell-type specific vacuole formation in the absence of canonical ATG5-dependent autophagy

Jose,

Sharma,

Insan

et al. 2023

Preprint

View full text Add to dashboard Cite

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Cytoskeleton disruption and plasma membrane damage determine methuosis of normal and malignant cells

Gao,

Dong,

Xiao

et al. 2024

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Methuosis represents a novel cell death modality characterized by catastrophic cytoplasmic vacuolization in normal and malignant cells. However, the critical role and the underlying mechanism of cytoskeleton and plasma membrane damage in methuotic cells are largely unknown. Herein, maduramicin-treated myocardial cells (H9c2) and indole chalcone-exposed glioma cells (U251) were used as methuosis model to uncover this secret. We found that cytoskeleton protein F-actin, α-tubulin, β-tubulin and filamin A/B were disrupted in a reversible-dependent manner. In addition, RhoA-ROCK1 signaling pathway mediated cytoskeleton disruption in methuotic cells. Excessive cytoplasmic vacuolization triggered cellular plasma membrane damage and the release of DAMPs, including LDH, ATP and CRT. Furthermore, at the end phase of methuotic cells, plasma membrane was damaged independent of pore-forming protein p-MLKL and GSDMD. Endosomal sorting complex required for transport (ESCRT)-Ⅲ especially its subunit CHMP3 and CHMP5 negatively regulated excessive vacuolization-induced plasma membrane damage in cells undergoing methuosis. In conclusion, for the first time, the critical role and potential mechanism of cytoskeleton and plasma membrane damage in methuotic cells are known, which would facilitate the employment of methuosis in life science and pharmacology.

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V-ATPase V0 subunit activation mediates maduramicin-induced methuosis through blocking endolysosomal trafficking in vitro and in vivo

Cited by 2 publications

References 48 publications

Kinase inhibitor-induced cell-type specific vacuole formation in the absence of canonical ATG5-dependent autophagy

Kinase inhibitor-induced cell-type specific vacuole formation in the absence of canonical ATG5-dependent autophagy

Cytoskeleton disruption and plasma membrane damage determine methuosis of normal and malignant cells

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