Control of gasdermin D oligomerization and pyroptosis by the Ragulator-Rag-mTORC1 pathway.
Cell
; 184(17): 4495-4511.e19, 2021 08 19.
Article
en 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).
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Proteínas de Unión al GTP Monoméricas
/
Proteínas de Unión a Fosfato
/
Péptidos y Proteínas de Señalización Intracelular
/
Proteínas Adaptadoras Transductoras de Señales
/
Multimerización de Proteína
/
Piroptosis
/
Diana Mecanicista del Complejo 1 de la Rapamicina
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Año:
2021
Tipo del documento:
Article