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

Marta Valenti, María Molina, View ORCID ProfileVíctor J Cid
doi: https://doi.org/10.1101/2022.11.29.518328
Marta Valenti
1Departamento de Microbiología y Parasitología, Facultad de Farmacia, and Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS); Universidad Complutense de Madrid; Madrid, 28040; Spain
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María Molina
1Departamento de Microbiología y Parasitología, Facultad de Farmacia, and Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS); Universidad Complutense de Madrid; Madrid, 28040; Spain
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  • For correspondence: molmifa@ucm.es vicjcid@ucm.es
Víctor J Cid
1Departamento de Microbiología y Parasitología, Facultad de Farmacia, and Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS); Universidad Complutense de Madrid; Madrid, 28040; Spain
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  • ORCID record for Víctor J Cid
  • For correspondence: molmifa@ucm.es vicjcid@ucm.es
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Summary

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 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 29, 2022.
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Human Gasdermin D and MLKL disrupt mitochondria, endocytic traffic and TORC1 signaling in budding yeast
Marta Valenti, María Molina, Víctor J Cid
bioRxiv 2022.11.29.518328; doi: https://doi.org/10.1101/2022.11.29.518328
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Human Gasdermin D and MLKL disrupt mitochondria, endocytic traffic and TORC1 signaling in budding yeast
Marta Valenti, María Molina, Víctor J Cid
bioRxiv 2022.11.29.518328; doi: https://doi.org/10.1101/2022.11.29.518328

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