Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway.
Cell
; 184(17): 4495-4511.e19, 2021 08 19.
Article
em En
| MEDLINE
| ID: mdl-34289345
ABSTRACT
The process of pyroptosis is mediated by inflammasomes and a downstream effector known as gasdermin D (GSDMD). Upon cleavage by inflammasome-associated caspases, the N-terminal domain of GSDMD forms membrane pores that promote cytolysis. Numerous proteins promote GSDMD cleavage, but none are known to be required for pore formation after GSDMD cleavage. Herein, we report a forward genetic screen that identified the Ragulator-Rag complex as being necessary for GSDMD pore formation and pyroptosis in macrophages. Mechanistic analysis revealed that Ragulator-Rag is not required for GSDMD cleavage upon inflammasome activation but rather promotes GSDMD oligomerization in the plasma membrane. Defects in GSDMD oligomerization and pore formation can be rescued by mitochondrial poisons that stimulate reactive oxygen species (ROS) production, and ROS modulation impacts the ability of inflammasome pathways to promote pore formation downstream of GSDMD cleavage. These findings reveal an unexpected link between key regulators of immunity (inflammasome-GSDMD) and metabolism (Ragulator-Rag).
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Proteínas Monoméricas de Ligação ao GTP
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Proteínas de Ligação a Fosfato
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Peptídeos e Proteínas de Sinalização Intracelular
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Proteínas Adaptadoras de Transdução de Sinal
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Multimerização Proteica
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Piroptose
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Alvo Mecanístico do Complexo 1 de Rapamicina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2021
Tipo de documento:
Article