Gasdermin D maintains bone mass by rewiring the endo-lysosomal pathway of osteoclastic bone resorption

Li, Mobai; Yang, Dehang; Yan, Huige; Tang, Zhibin; Jiang, Danlu; Zhang, Jian; Chi, Zhexu; Nie, Wanyun; Zhen, Wenxuan; Yu, Weiwei; Chen, Sheng; Wang, Zhen; Yu, Qianzhou; Zhang, Xue; Yang, Fan; Fan, Shunwu; Lin, Xianfeng; Wang, Di

doi:10.1016/j.devcel.2022.09.013

Cited by 25 publications

(22 citation statements)

References 47 publications

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“…The vesicular traffic machinery is also necessary to lead Atg8 to the vacuole during autophagy [62,63]. Besides, several previous reports have related GSDMD and MLKL function to perturbations in the endosomal transport [20][21][22][27][28][29][30]. Overall, our results suggested that GSDMD(NT) and all the MLKL constructs tested could be interfering with yeast endosomal traffic, consequently inhibiting TORC1 while hampering autophagy.…”

Section: The Ntds Of Gsdmd and Mlkl Distinctly Disrupt Endosomal Trafficsupporting

confidence: 64%

“…In a screening aimed at identifying GSDMD(NT) regulators, several genes associated with the endosomal and vacuolar organization were detected in macrophages [21]. Another study identified that several proteins related to lysosomal function and trafficking were up-regulated in GSDMD-deleted osteoclasts [22]. Besides, the ESCRT-III system, which seems to be affected in yeast by GSDMD(NT) expression, is necessary for the repair of the plasma membrane and downregulation of pyroptosis [76].…”

Section: Discussionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted November 29, 2022. ; https://doi.org/10.1101/2022.11.29.518328 doi: bioRxiv preprint MLKL and GSDMD(NT) show affinity for phosphoinositides, preferentially for phosphatidylinositol-4-phosphate [PI(4)P] and phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ], typical of the plasma membrane [10,80,81], also for phosphatidylinositol-3phosphate [PI(3)P] and phosphatidylinositol-3,5-bisphosphate [PI(3,5)P 2 ], which are present in yeast early and late endosomes, respectively [5,22]. As the concentration of PI(3)P and PI(3,5)P 2 is higher in yeast endosomal compartments compared to those of mammalian cells [73], GSDMD and MLKL might be hijacked to endosomal vesicles in yeast, preventing them from localizing at the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

“…Cells die as a consequence of the loss of membrane selective permeability [7]. However, the plasma membrane is not the only target of GSDMD, as it damages other internal structures, such as mitochondria [15][16][17][18][19] or endosomes [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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Human Gasdermin D and MLKL disrupt mitochondria, endocytic traffic and TORC1 signaling in budding yeast

Valenti

Molina

Cid

2022

Preprint

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Gasdermin D (GSDMD) and mixed lineage kinase domain-like protein (MLKL) are the pore-forming effectors of pyroptosis and necroptosis, respectively, with the capacity to disturb plasma membrane selective permeability and induce programmed cell death. The budding yeastSaccharomyces cerevisiaehas long been used as a simple eukaryotic model for the study of proteins associated with human diseases by heterologous expression. In this work, we expressed in yeast both GSDMD and its N-terminal domain [GSDMD(NT)] to characterize their cellular effects and compare them to those of MLKL. GSDMD(NT) and MLKL inhibited yeast growth, formed cytoplasmic aggregates, and fragmented mitochondria. Loss-of-function point mutants of GSDMD(NT) showed affinity for this organelle. Besides, GSDMD(NT) and MLKL caused an irreversible cell cycle arrest through TORC1 inhibition and disrupted endosomal and autophagic vesicular traffic. Our results provide a basis for a humanized yeast platform to study GSDMD and MLKL, a useful tool for structure-function assays and drug discovery.

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Section: The Ntds Of Gsdmd and Mlkl Distinctly Disrupt Endosomal Trafficsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Human Gasdermin D and MLKL disrupt mitochondria, endocytic traffic and TORC1 signaling in budding yeast

Valenti

Molina

Cid

2022

Preprint

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

Human gasdermin D and MLKL disrupt mitochondria, endocytic traffic and TORC1 signalling in budding yeast

2023

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Gasdermin D (GSDMD) and mixed lineage kinase domain-like protein (MLKL) are the pore-forming effectors of pyroptosis and necroptosis, respectively, with the capacity to disturb plasma membrane selective permeability and induce regulated cell death. The budding yeast Saccharomyces cerevisiae has long been used as a simple eukaryotic model for the study of proteins associated with human diseases by heterologous expression. In this work, we expressed in yeast both GSDMD and its N-terminal domain (GSDMD(NT)) to characterize their cellular effects and compare them to those of MLKL. GSDMD(NT) and MLKL inhibited yeast growth, formed cytoplasmic aggregates and fragmented mitochondria. Loss-of-function point mutants of GSDMD(NT) showed affinity for this organelle. Besides, GSDMD(NT) and MLKL caused an irreversible cell cycle arrest through TORC1 inhibition and disrupted endosomal and autophagic vesicular traffic. Our results provide a basis for a humanized yeast platform to study GSDMD and MLKL, a useful tool for structure–function assays and drug discovery.

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Gasdermin‐E‐Dependent Non‐Canonical Pyroptosis Promotes Drug‐Induced Liver Failure by Promoting CPS1 deISGylation and Degradation

Ouyang,

Zhu,

Cao

et al. 2024

Advanced Science

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Drug‐induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non‐canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP‐DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP‐DILI. Mice with hepatocyte‐specific rescue of GSDME reproduced APAP‐induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP‐induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte‐derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte‐specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon‐stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase‐1 (CPS1), promoted its degradation via K48‐linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl‐fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP‐DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP‐DILI.

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Gasdermin D maintains bone mass by rewiring the endo-lysosomal pathway of osteoclastic bone resorption

Cited by 25 publications

References 47 publications

Human Gasdermin D and MLKL disrupt mitochondria, endocytic traffic and TORC1 signaling in budding yeast

Human Gasdermin D and MLKL disrupt mitochondria, endocytic traffic and TORC1 signaling in budding yeast

Human gasdermin D and MLKL disrupt mitochondria, endocytic traffic and TORC1 signalling in budding yeast

Gasdermin‐E‐Dependent Non‐Canonical Pyroptosis Promotes Drug‐Induced Liver Failure by Promoting CPS1 deISGylation and Degradation

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